Catheter-assisted tumor treatment

ABSTRACT

A method for treating a subject diagnosed with a cancer or other disorder comprising a hyperproliferative tissue is described herein. The method includes localized delivery of a material which contains a therapeutically effective agent and/or moiety. The localized delivery of the agent is achieved using a catheter-based delivery system and an implant. An implant can include a support component, a cover component, and a valve component. The valve component can be operable to permit flow through the implant. The implant can be delivered on a catheter, with one of the ends of the implant being selectively expanded to permit temporary occlusion of a vessel while delivering a material through the valve component to a downstream target region. The other end of the implant can thereafter be released such that the implant occludes the vessel, or the implant can be removed from the vessel entirely.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of U.S. patent applicationSer. No. 14/101,171, filed on Dec. 9, 2013, which claims the prioritybenefit of U.S. Provisional Application Nos. 61/835,406, filed Jun. 14,2013, 61/835,461, filed Jun. 14, 2013, and 61/900,321, filed Nov. 5,2013, the entirety of each of which is incorporated herein by reference.

CROSS-REFERENCE TO A SEQUENCE LISTING

A “Sequence Listing” is submitted with this application in the form of atext file, created Dec. 17, 2015, and named “0865380074seqlist.txt”(20912 bytes), the contents of which are incorporated herein byreference in their entirety

BACKGROUND

1. Field of the Inventions

The present disclosure is related to endovascular apparatuses andmethods, and more specifically, to apparatuses and methods fordelivering embolic and therapeutic materials to a target region of abody lumen and regulating blood flow therethrough. Also disclosed hereinare methods for treating a subject diagnosed with a cancer byadministering to the subject therapeutic materials using the devices andmethods described herein.

2. Description of the Related Art

Blood vessels can be accessed to deploy embolic agents, contrast agents,and medications to target regions of the body. Some target regionsinclude the blood vessels themselves, as well as organs or other tissuebeing fed by blood vessels.

For example, through embolization, blood flow can be reduced toencourage atrophy or infarction of a target region of the body. Suchtarget regions can include tumors, fibroids, and vascular malformations,such as arteriovenous malformations (“AVM”) or arteriovenous fistulas(“AVF”). Further, embolization of blood vessels can also be achieved toslow or stop bleeding in emergency situations.

Embolic agents and therapeutic agents can be used to treat cancer. Forexample, embolics can be used to occlude the vasculature feeding atumor. Drug-loaded embolics, such as drug-loaded microspheres, can beused to deliver chemotherapeutic agents and/or therapeutic agentsdesigned to treat inflamed or diseased tissue. In addition, clinicianshave administered chemotherapeutic agents in combination with embolicpolyvinyl alcohol (“PVA”) particles. This type of targeted therapy canlocalize treatment at the site of the tumor and minimize the systemicdose while maximizing the therapeutic dose delivered locally to thetarget lesion, reducing potential side effects and damage to healthytissue.

SUMMARY

Various embodiments of medical methods and apparatus disclosed hereinenable a clinician to provide a targeted delivery of a material, such asan embolic material, contrast agent, or drug, to a select body region.Some embodiments relate to vessel occlusion and tissue ablation orinfarction by delivery of radially expandable implant frames that can beused to deliver a material to a downstream target area, such as a bloodvessels or tissue. In some embodiments, the implant can be positioned toachieve immediate total occlusion of blood flow to ensure high materialconcentration in the target area, precise or calibrated control ofdelivered material, and specific targeting of certain structures andprotection of others, which is especially useful for smaller targetvessels and tissues. Some embodiments also provide for secondaryprocedures to be performed after an initial implant and material hasbeen deployed at a target region. Furthermore, some embodiments of thepresent system can help close a bodily lumen or vessel rapidly and withconfidence. These various advantages and benefits can provide improvedhealth and quality of life for millions of people.

In accordance with some embodiments, various frame configurations,expected delivered and expanded dimensions, and a description of targetanatomy of some embodiments are provided. Aspects of implants anddelivery devices that can be utilized in combination with the implantsand features disclosed herein are disclosed in applicant's co-pendingU.S. patent application Ser. No. 14/044,794, filed on Oct. 2, 2013; U.S.Patent Application No. 61/904,376, filed Nov. 14, 2013, titledImplantable Luminal Devices and Methods (086538-0041); U.S. PatentApplication No. 61/904,379, filed on Nov. 14, 2013, titled TorqueResistant Distal Catheter Tip (086538-0043); U.S. patent applicationSer. No. 12/906,993, filed on Oct. 18, 2010; and U.S. patent applicationSer. No. 13/828,974, filed on Mar. 14, 2013, U.S. Patent Application No.61/835,406, filed on Jun. 14, 2013, and U.S. Patent Application No.61/835,461, filed on Jun. 14, 2013, the entireties of which areincorporated herein by reference.

Some embodiments can provide vascular implantation for vessels that arefrom about 2 mm to about 16 mm, from about 5 mm to about 13 mm, and insome embodiments, from about 7 mm to about 11 mm. The target deliveryprofile can be from about 2 Fr to about 8 Fr, about 3 Fr to about 7 Fr,from about 4 Fr to about 6 Fr, or in some embodiments, about 5 Fr.Additionally, expansion of the implant can provide sufficient radialforce against the inside wall of a vein. Some embodiments can comprisefeatures or means configured to minimize backflow of blood or minimizevenous insufficiency. For example, treatment applications forembodiments of the implant can include ilio-femoral venous obstructionand chronic iliac venous outflow obstruction as a result of venousdisease.

Further, in some embodiments, the implant can provide enhanced controlof the delivery of a material or agent. For example, in accordance withan aspect of some embodiments is the realization that the delivery anddistribution of a material can depend exclusively upon distal flowpatterns. Some embodiments disclosed herein can enable control ofmaterial delivery, prevent reflux of the material, and permit calibrateddelivery of the material, which can often be limited by early refluxalong a delivery platform. The material can comprise liquid embolicagents such as N-butyl cyanoacrylate (“NBCA”), Onyx, or other liquidagents, radioembolization particles, and microspheres, such asmicrospheres filled with the radioactive isotope Yttrium Y-90.

The subject technology is illustrated, for example, according to variousaspects described below. Various examples of aspects of the subjecttechnology are described as numbered clauses (1, 2, 3, etc.) forconvenience. These are provided as examples and do not limit the subjecttechnology. It is noted that any of the dependent clauses may becombined in any combination, and placed into a respective independentclause, e.g., clause 1 or clause 5. The other clauses can be presentedin a similar manner.

Clause 1. A material delivery device, comprising: an expandable supportmember having a lumen and an outflow end, the support member beingconfigured to expand from a collapsed configuration to an expandedconfiguration for placement in a body lumen; a cover component,extending along the support member, defining an aperture; and a valvecomponent coupled to the cover component and disposed at the outflowend, the valve component permitting outflow of a material through theaperture and restricting backflow of the material into the aperture.

Clause 2. The device of Clause 1, wherein the cover component comprisesa tubular membrane coupled to the support member and the valve componentcomprises a free end of the tubular membrane extending away from thesupport member at the outflow end, the free end of the tubular membranebeing configured to permit outflow of the material through the outflowend and to invert or fold onto itself to restrict backflow of thematerial into the outflow end.

Clause 3. The device of any one of Clauses 1 to 2, wherein the tubularmembrane comprises inner and outer portions that extend along respectiveinterior and exterior surfaces of the support member.

Clause 4. The device of Clause 3, wherein the free end of the tubularmembrane extends from the outer portion, and the inner portion comprisesa second free end.

Clause 5. The device of Clause 4, wherein the free end is coupled to thesecond free end.

Clause 6. The device of any one of Clauses 1 to 5, wherein the covercomponent comprises a tubular membrane coupled to the support member andthe valve component comprises a free end of the tubular membraneextending away from the support member at the outflow end, wherein thetubular membrane comprises a tubular outer portion extending along asupport member exterior and a segmented inner portion, comprising aplurality of strips, extending along a support member interior.

Clause 7. The device of Clause 6, wherein the free end is coupled to atleast one of the plurality of strips.

Clause 8. The device of Clause 7, wherein the coupling comprises asuture.

Clause 9. The device of any one of Clauses 1 to 8, wherein the valvecomponent is movable between open and closed positions, the valvecomponent permitting flow of the material through the outflow end whenin the open position and restricting backflow of the material throughthe outflow end when in the closed position.

Clause 10. The device of Clause 9, wherein in the open position, atleast a portion of the valve component is spaced apart from the apertureto permit flow through the aperture.

Clause 11. The device of Clause 9, wherein in the closed position, thevalve component has a sealing relationship with at least one of thesupport member or cover component to close the aperture at leastpartially and restrict flow through the device.

Clause 12. The device of any one of Clauses 1 to 11, wherein the valvecomponent comprises a mesh material.

Clause 13. The device of Clause 12, wherein the mesh material is coupledto an outer surface of the cover component adjacent to the outflow end.

Clause 14. The device of any one of Clauses 1 to 13, wherein the valvecomponent comprises a flap structure coupled to the cover componentadjacent the outflow end, the flap structure being movable away from theaperture to permit flow therethrough.

Clause 15. The device of any one of Clauses 1 to 14, wherein the valvecomponent comprises a plurality of deflectable panels.

Clause 16. The device of any one of Clauses 1 to 15, wherein the valvecomponent comprises a split dome.

Clause 17. The device of any one of Clauses 1 to 16, wherein the supportmember comprises a helical body.

Clause 18. The device of any one of Clauses 1 to 17, wherein the supportmember comprises a deflectable frame configured to expand from asubstantially linear collapsed configuration to the expandedconfiguration.

Clause 19. A method of delivering a material to a target region of abody lumen, comprising: advancing an implant to the target region, theimplant having first and second sections engaged with a catheter atrespective first and second engagement points; releasing the implantfirst section from engagement with the catheter at the first engagementpoint; permitting the implant first section to expand against a lumenwall at the target region such that the lumen becomes at leastsubstantially occluded; and injecting a material through a portion ofthe implant.

Clause 20. The method of Clause 19, wherein the implant first sectioncomprises an implant distal section, and wherein the releasing comprisesdisengaging a first engagement member from the distal section.

Clause 21. The method of Clause 20, wherein the portion of the implantcomprises a valve component and the permitting comprises causing thevalve component to contact a distal end of the catheter such that thecatheter distal end moves the valve component to an open position.

Clause 22. The method of Clause 21, wherein the injecting comprisesadvancing the material out through the valve component after the valvecomponent is in the open position.

Clause 23. The method of any one of Clauses 19 to 22, furthercomprising, after the material is injected into the lumen, releasing theimplant second section and moving the catheter proximally relative tothe implant such that the valve component moves to a closed position.

Clause 24. The method of Clause 23, wherein the moving the catheterrelative to the implant comprises proximally withdrawing the catheterwithin the lumen.

Clause 25. The method of any one of Clauses 19 to 24, wherein theimplant first section comprises a proximal section, and wherein thereleasing comprises disengaging a first engagement member from theproximal section.

Clause 26. The method of Clause 25, wherein the permitting furthercomprises flushing the implant with a fluid to facilitate expansion ofthe proximal section.

Clause 27. The method of any one of Clauses 19 to 26, further comprisingreleasing the implant second section into apposition with the lumen wallsuch that the implant is disengaged from the catheter.

Clause 28. The method of any one of Clauses 19 to 27, further comprisingproximally withdrawing the assembly from the lumen.

Clause 29. The method of Clause 28, wherein the withdrawing compriseswithdrawing the assembly into a guide catheter such that expanded firstsection collapses within the guide catheter.

Clause 30. The method of any one of Clauses 19 to 29, furthercomprising, prior to releasing the implant first section, releasing ablocking implant into contact against the lumen wall downstream of thetarget region, the blocking implant occluding flow through the lumenbeyond the target region.

Clause 31. The method of Clause 30, further comprising, after injectinga material, allowing the material to flow into the target region, andremoving the blocking implant from the lumen.

Clause 32. A method of delivering a material to a target region of abody lumen, comprising: removing an occlusion at a distal end of animplant, deployed within the lumen upstream of the target region,thereby restoring flow through the lumen to the target region; and afterremoving the occlusion from the implant, injecting a material into thelumen such that the material passes through the implant to the targetregion.

Clause 33. The method of Clause 32, wherein contacting the implantcomprises advancing an adjustment member through the implant to pierce acover component of the implant.

Clause 34. The method of Clause 33, wherein the adjustment membercomprises a catheter and the advancing comprises advancing the catheterthrough the implant to pierce a cover component of the implant.

Clause 35. The method of any one of Clauses 32 to 34, wherein theimplant is a first implant, and the method further comprises: aftercontacting the first implant, advancing a second implant to the targetregion, the second implant having first and second sections engaged witha catheter at respective first and second engagement points; releasingthe first section from engagement with the catheter at the firstengagement point; and before injecting a material, permitting theimplant first section to expand against a lumen wall at the targetregion such that the lumen becomes at least substantially occluded.

Clause 36. The method of Clause 35, further comprising releasing thesecond implant adjacent to the first implant.

Clause 37. The method of Clause 35, further comprising releasing thesecond implant within the first implant.

Clause 38. The method of any one of Clauses 32 to 37, wherein contactingthe first implant comprises contacting a mesh component of the firstimplant with a material to dissolve coagulated material on the meshcomponent, thereby restoring flow through the mesh component.

Clause 39. A delivery assembly, for delivering an expandable member to abody lumen or luminal structure of a patient, comprising: a carriermember, positionable in a luminal structure of a patient, comprising alumen having a cross-sectional area comprising a first portion and asecond portion that are separated by a line segment intersecting acircumference of the carrier member, the carrier member comprising aslot extending through the carrier member into the lumen and bounded bythe line segment and the circumference, within the first portion; anelongate member extending through the carrier lumen and across the slot;and an expandable member configured to expand within and engage theluminal structure, the expandable member comprising a coupling portionthat fits within the slot, the coupling portion comprising an apertureconfigured to receive the elongate member therethrough when the couplingportion is positioned within the slot; wherein the elongate member isconfigured to move axially through the carrier lumen to be removed fromthe aperture and permit release of the coupling portion from the slot.

Clause 40. The assembly of Clause 39, wherein the carrier lumen extendsto and is open at a distal end of the carrier member.

Clause 41. The assembly of any one of Clauses 39 to 40, wherein thecarrier member comprises a second slot, distal to the slot, configuredto receive a distal coupling portion of the expandable member.

Clause 42. The assembly of Clause 41, wherein the distal couplingportion comprises an aperture configured to receive an elongate membertherethrough when the distal coupling portion is positioned within thesecond slot.

Clause 43. The assembly of any one of Clauses 39 to 42, wherein theelongate member is configured to be retracted by an operator such thatthe elongate member permits the release of the first portion.

Clause 44. The assembly of any one of Clauses 39 to 43, wherein the slotcomprises a slot depth of between about ⅓ and about ⅔ of a carriermember diameter or of about ½ of a carrier member diameter.

Clause 45. The assembly of any one of Clauses 39 to 44, wherein thedevice further comprises an optical fiber which is positioned within thefirst or second portion of the carrier lumen and which extends thelength of the carrier lumen.

Clause 46. The assembly of any one of Clauses 39 to 45, furthercomprising a cover member extending at least partially over theexpandable member.

Clause 47. The assembly of any one of Clauses 39 to 46, wherein the slotcomprises distal and proximal faces that extend in substantiallyparallel planes, the slot defining a slot width between the distal andproximal faces.

Clause 48. The assembly of Clause 47, wherein the distal and proximalfaces extend substantially perpendicularly relative to a longitudinalaxis of the carrier member.

Clause 49. The assembly of Clause 47, wherein the distal and proximalfaces are obliquely oriented relative to a longitudinal axis of thecarrier member.

Clause 50. The assembly of any one of Clauses 39 to 49, wherein thecoupling portion comprises a flat cross-sectional shape.

Clause 51. The assembly of any one of Clauses 39 to 50, wherein the slotwidth is less than twice a thickness of the coupling portion.

Clause 52. An expandable implant, for placement in a body lumen orluminal structure of a patient via a carrier member, comprising: anexpandable member configured to expand within and engage the body lumen,the expandable member comprising proximal and distal end portions, theproximal end portion comprising an aperture configured to receive anelongate member therethrough for coupling the proximal end portionrelative to a carrier member for delivery to the body lumen; and a covermember extending at least partially over the proximal and distal endportions, the cover member comprising an open end for permitting fluidflow therethrough.

Clause 53. The implant of Clause 52, wherein the expandable membercomprises a coil.

Clause 54. The implant of any one of Clauses 52 to 53, wherein theexpandable member comprises a flat coil.

Clause 55. The implant of any one of Clauses 52 to 54, wherein theexpandable member comprises a flat coil and the aperture extendsradially through the proximal end portion of the flat coil.

Clause 56. The implant of Clause 55, wherein the proximal end portioncomprises a substantially planar portion, the aperture extending througha center of the proximal end portion.

Clause 57. The implant of any one of Clauses 52 to 56, wherein theproximal end portion defines an average width that is approximatelyequal to an average width of the expandable member between the proximaland distal end portions.

Clause 58. The implant of any one of Clauses 52 to 57, wherein thedistal end portion comprises a second aperture configured to receive anelongate member therethrough for coupling the distal end portionrelative to the carrier member for delivery to the body lumen.

Clause 59. The implant of Clause 58, wherein the distal end portioncomprises a substantially planar portion, the second aperture extendingthrough a center of the distal end portion.

Clause 60. The implant of any one of Clauses 52 to 57, furthercomprising an optical fiber extending along the carrier member.Optionally, the optical fiber can be encased within the carrier member.For example, the optical fiber can extend within a lumen of the carriermember. Further, the optical fiber can optionally be co-molded orover-molded with the carrier member. Furthermore, the optical fiber canbe separate from the carrier member and delivered either with orseparately from (e.g., after the carrier member has been inserted to adelivery position or removed entirely after delivery of a material tothe target area).

Clause 61. A method of delivering an expandable member to a luminalstructure of a patient, comprising: advancing a carrier member through aluminal structure of a patient to a target area, the carrier memberbeing coupled to an expandable member via an elongate member, theelongate member extending through a lumen of the carrier member toengage an end portion of the expandable member within a slot of thecarrier member; proximally retracting the elongate member from anaperture of the end portion to release the end portion; and permittingrelease of the expandable member against the luminal structure.

Clause 62. The method of Clause 61, further comprising proximallyretracting an elongate member from a second aperture of a second endportion of the expandable member.

Clause 63. The method of any one of Clauses 62 to 62, wherein theproximally retracting comprises proximally retracting a second elongatemember from a second aperture of a second end portion of the expandablemember.

Clause 64. The method of any one of Clauses 61 to 63, performed incombination with the method of any one of Clauses 19 to 38.

Clause 65. The method of any one of Clauses 61 to 64, performed usingthe implant of any one of Clauses 1 to 18 or Clauses 52 to 59.

Clause 66. The method of any one of Clauses 60 to 64, performed usingthe assembly of any one of Clauses 39 to 51.

Clause 67. A method of manufacturing an expandable member for deliveryinto a luminal structure of a patient via a carrier member, comprising:positioning an expandable member onto a carrier member; placing an endportion of the expandable member into a slot of the carrier member; andinserting an elongate member into an aperture of the end portion toengage the end portion within the slot.

Clause 68. The method of Clause 67, wherein the end portion comprises aflat cross-sectional shape, and the placing the end portion comprisestwisting the end portion such that the flat shape is aligned with theslot, in a side, cross-sectional view.

Clause 69. The method of Clause 68, wherein the slot comprises distaland proximal faces extending in a substantially parallel planes.

Clause 70. The method of Clause 69, wherein the substantially parallelplanes are oriented substantially perpendicular relative to alongitudinal axis of the carrier member.

Clause 71. The method of Clause 69, wherein the substantially parallelplanes are obliquely oriented relative to a longitudinal axis of thecarrier member.

Clause 72. The method of any one of Clauses 67 to 71, furthercomprising: placing a second end portion of the expandable member into asecond slot of the carrier member; and inserting a second elongatemember into a second aperture of the second end portion to engage thesecond end portion within the slot.

Clause 73. The method of any one of Clauses 67 to 72, performed usingthe implant of any one of Clauses 1 to 18 or Clauses 52 to 59.

Clause 74. The method of any one of Clauses 67 to 73, performed usingthe assembly of any one of Clauses 39 to 51.

Clause 75. A method for treating a subject, comprising: advancing animplant to a target region of a body lumen, the implant being engagedwith a catheter; releasing the implant first section from engagementwith the catheter; permitting the implant to expand against a lumen wallat the target region such that the lumen becomes at least substantiallyoccluded; and injecting a therapeutic material through a portion of theimplant, wherein the material is therapeutically effective to treat thesubject. For example, the method can be used for treating a subject andcomprise: advancing an implant to a target region of a body lumen, theimplant having first and second sections engaged with a catheter atrespective first and second engagement points; releasing the implantfirst section from engagement with the catheter at the first engagementpoint; permitting the implant first section to expand against a lumenwall at the target region such that the lumen becomes at leastsubstantially occluded; and injecting a therapeutic material through aportion of the implant, wherein the material is therapeuticallyeffective to treat the subject. In some embodiments, the method can beused to treat a subject diagnosed with a cancer. For example, the targetregion can be located adjacent to or contain the cancer. Further, thetherapeutic material injected can be effective to treat the cancer.

Clause 76. The method of Clause 76, wherein the implant first sectioncomprises an implant distal section, and wherein the releasing comprisesdisengaging a first engagement member from the distal section.

Clause 77. The method of Clause 76, wherein the portion of the implantcomprises a valve component and the permitting comprises causing thevalve component to contact a distal end of the catheter such that thecatheter distal end moves the valve component to an open position.

Clause 78. The method of Clause 77, wherein the injecting comprisesadvancing the material out through the valve component after the valvecomponent is in the open position.

Clause 79. The method of any one of Clauses 75 to 78, furthercomprising, after the material is injected into the lumen, releasing theimplant second section and moving the catheter proximally relative tothe implant such that the valve component moves to a closed position.

Clause 80. The method of Clause 79, wherein the moving the catheterrelative to the implant comprises proximally withdrawing the catheterwithin the lumen.

Clause 81. The method of any one of Clauses 75 to 80, wherein theimplant first section comprises a proximal section, and wherein thereleasing comprises disengaging a first engagement member from theproximal section.

Clause 82. The method of Clause 81, wherein the permitting furthercomprises flushing the implant with a fluid to facilitate expansion ofthe proximal section.

Clause 83. The method of any one of Clauses 75 to 82, further comprisingreleasing the implant second section into apposition with the lumen wallsuch that the implant is disengaged from the catheter.

Clause 84. The method of any one of Clauses 75 to 83, further comprisingproximally withdrawing the assembly from the lumen.

Clause 85. The method of Clause 84, wherein the withdrawing compriseswithdrawing the assembly into a guide catheter such that expanded firstsection collapses within the guide catheter.

Clause 86. The method of any one of Clauses 75 to 85, furthercomprising, prior to releasing the implant first section, releasing ablocking implant into contact against the lumen wall downstream of thetarget region, the blocking implant occluding flow through the lumenbeyond the target region.

Clause 87. The method of Clause 86, further comprising, after injectingthe material, allowing the material to flow into the target region, andremoving the blocking implant from the lumen.

Clause 88. The method of any one of Clauses 75 to 87, wherein thetherapeutic material comprises a nanoparticle, a radioemboliccomposition, a blood substitute comprising oxygen, a photothermal agent,or a chemotherapeutic.

Clause 89. The method of Clause 88, wherein the nanoparticle comprises agold nanoparticle or a gold-iron oxide alloy nanoparticle.

Clause 90. The method of Clause 88 or 89, wherein the nanoparticle islinked to a pH low-insertion peptide or to an antibody which binds anantigen expressed on a cell of a cancer.

Clause 91. The method of any one of Clauses 75 to 90, further comprisingactivating an optical fiber to emit electromagnetic radiation. In someembodiments, the optical fiber extends from the proximal to the distalend of the catheter. In some other embodiments, the optical fiber canemit infrared light at its distal end. For example, the optical fibercan be coupled to the catheter and can be controlled independently toemit light to the target region.

Clause 92. The method of Clause 91, wherein the optical fiber isactivated to emit infrared light at its distal end after injecting thematerial into the target region.

Clause 93. The method of Clause 91, wherein the optical fiber isactivated to emit infrared light at its distal end after injecting thematerial into the target region and before moving the blocking implantfrom the lumen.

Clause 94. The method of any one of Clauses 75 to 87, wherein thetherapeutic material comprises a radiosensitizer.

Clause 95. The method of Clause 94, wherein the radiosensitizercomprises a blood substitute comprising oxygen.

Clause 96. The method of Clause 94 or 95, further comprisingadministering to the subject x-irradiation or γ-irradiation, wherein thex-irradiation or γ-irradiation is administered externally or isadministered internally through the catheter to the target region.

Clause 97. A method for treating a subject, comprising: removing anocclusion at a distal end of an implant deployed within a body lumenupstream of a target region, thereby restoring flow through the lumen tothe target region; and after removing the occlusion from the implant,injecting a therapeutic material into the lumen such that the materialpasses through the implant to the target region, wherein the therapeuticmaterial is effective to treat the subject. In some embodiments, themethod can be used to treat a subject diagnosed with a cancer. Forexample, the target region can be located adjacent to or contain thecancer. Further, the therapeutic material injected can be effective totreat the cancer.

Clause 98. The method of Clause 97, wherein contacting the implantcomprises advancing an adjustment member through the implant to pierce acover component of the implant.

Clause 99. The method of Clause 98, wherein the adjustment membercomprises a catheter and the advancing comprises advancing the catheterthrough the implant to pierce a cover component of the implant.

Clause 100. The method of any one of Clauses 97 to 99, wherein theimplant is a first implant, and the method further comprises: aftercontacting the first implant, advancing a second implant to the targetregion, the second implant having first and second sections engaged witha catheter at respective first and second engagement points; releasingthe first section from engagement with the catheter at the firstengagement point; and before injecting the therapeutic material,permitting the implant first section to expand against a lumen wall atthe target region such that the lumen becomes at least substantiallyoccluded.

Clause 101. The method of Clause 100, further comprising releasing thesecond implant adjacent to the first implant.

Clause 102. The method of Clause 100, further comprising releasing thesecond implant within the first implant.

Clause 103. The method of any one of Clauses 97 to 102, whereincontacting the first implant comprises contacting a mesh component ofthe first implant with a material to dissolve coagulated material on themesh component, thereby restoring flow through the mesh component.

Clause 104. The method of any one of Clauses 97 to 103, wherein thetherapeutic material comprises a nanoparticle, a radioemboliccomposition, a blood substitute comprising oxygen, a photothermal agent,or a chemotherapeutic.

Clause 105. The method of Clause 104, wherein the nanoparticle comprisesa gold nanoparticle or a gold-iron oxide alloy nanoparticle.

Clause 106. The method of Clause 104 or 105, wherein the nanoparticle islinked to a pH low-insertion peptide or to an antibody which binds anantigen on expressed on a cell of a cancer.

Clause 107. The method of any one of Clauses 97 to 106, wherein thecatheter encases an optical fiber which extends from the proximal to thedistal end of the catheter and wherein the optical fiber can emitinfrared light at its distal end.

Clause 108. The method of Clause 107, wherein the optical fiber isactivated to emit infrared light at its distal end after injecting thematerial into the target region.

Clause 109. The method of Clause 107, wherein the optical fiber isactivated to emit infrared light at its distal end after injecting thematerial into the target region and before moving the blocking implantfrom the lumen.

Clause 110. The method of any one of Clauses 97 to 103, wherein thetherapeutic material comprises a radiosensitizer.

Clause 111. The method of Clause 94, wherein the radiosensitizercomprises a blood substitute comprising oxygen.

Clause 112. The method of Clause 94 or 95, further comprisingadministering to the subject x-irradiation or γ-irradiation, wherein thex-irradiation or γ-irradiation is administered externally or internallythrough the catheter to the target region.

Clause 113. The implants, assemblies, or methods of any of the precedingClauses, wherein a slot width, slot depth, catheter lumen innerdiameter, catheter lumen inner diameter, engagement component diameter,aperture diameter, proximal end portion width, or proximal end portionthickness is within any of the corresponding ranges disclosed herein.

Additional features and advantages of the subject technology will be setforth in the description below, and in part will be apparent from thedescription, or may be learned by practice of the subject technology.The advantages of the subject technology will be realized and attainedby the structure particularly pointed out in the written description andembodiments hereof as well as the appended drawings.

It is to be understood that both the foregoing general description andthe following detailed description are exemplary and explanatory and areintended to provide further explanation of the subject technology.

BRIEF DESCRIPTION OF THE DRAWINGS

The accompanying drawings, which are included to provide furtherunderstanding of the subject technology and are incorporated in andconstitute a part of this specification, illustrate aspects of thesubject technology and together with the description serve to explainthe principles of the subject technology.

FIG. 1 is a perspective view of an implant carrier assembly, accordingto some embodiments.

FIG. 2 illustrates a perspective view of another implant carrierassembly, according to some embodiments.

FIG. 3 is a perspective view of an implant having a valve component,according to some embodiments.

FIG. 4 is a perspective view of the implant of FIG. 3, illustrating asupport component thereof, according to some embodiments.

FIG. 5A is a perspective view of a support frame mounted on a catheter,according to some embodiments.

FIG. 5B is an end view of the catheter and support frame of FIG. 5A,according to some embodiments.

FIG. 6A is a perspective view of a support frame mounted on a catheter,according to some embodiments.

FIG. 6B is an end view of the catheter and support frame of FIG. 6A,according to some embodiments.

FIGS. 6C-6E are side, cross-sectional views of an aperture that extendsthrough the catheter and engagement of an end of the support frametherein, according to some embodiments.

FIGS. 7A-7B are side, cross-sectional views of positions of an implantassembly having a valve component, according to some embodiments.

FIGS. 7C-7D are side, cross-sectional views of the implant assembly ofFIGS. 6A-6B subsequent to deployment and illustrating the closurethereof, according to some embodiments.

FIGS. 8A-8D are side, cross-sectional views of positions of an implantassembly having a mesh-type valve component, according to someembodiments.

FIGS. 9A-9B are side, cross-sectional views of positions of an implantassembly having a valve component, according to some embodiments.

FIGS. 10A-10B are side, cross-sectional views of positions of an implantassembly having a valve component, according to some embodiments.

FIGS. 11A-11B are side, cross-sectional views of positions of an implantassembly having a valve component, according to some embodiments.

FIGS. 12A-12B are side, cross-sectional views of positions of an implantassembly having a valve component, according to some embodiments.

FIG. 13 shows a perspective view of a frame in a compressed state withina deliver catheter, according to some embodiments.

FIG. 14A shows a perspective view of a frame partially expanded from adelivery catheter, according to some embodiments.

FIGS. 14B-14C are perspective views of an implant having a valvecomponent, according to some embodiments.

FIGS. 15A-15B are perspective views of an implant having a valvecomponent, according to some embodiments.

FIGS. 16A-16B are perspective views of an implant having a valvecomponent, according to some embodiments.

FIGS. 17A-17D are cross-sectional schematic views illustrating processesof depositing embolic particles into a target vessel region, accordingto some embodiments.

FIGS. 18A-18D are cross-sectional schematic views illustrating anotherprocess of depositing embolic particles into a target vessel region,according to some embodiments.

FIGS. 19A-19C are cross-sectional schematic views illustrating anotherprocess of depositing embolic particles into a target vessel region,according to some embodiments.

FIGS. 20A-20D are cross-sectional schematic views illustrating anotherprocess of depositing embolic particles into a target vessel region,according to some embodiments.

FIG. 21 is a cross-sectional schematic view illustrating deposition ofembolic particles into a target vessel region, according to someembodiments.

FIG. 22 is a cross-sectional schematic view illustrating deposition ofembolic particles into a target vessel region, according to someembodiments.

FIGS. 23A-23B illustrate schematic views illustrating alteration of animplanted occlusive device, according to some embodiments.

FIGS. 24A-24B illustrate schematic views illustrating alteration of animplanted first occlusive device and the insertion of a second deviceinto the first device, according to some embodiments.

DETAILED DESCRIPTION

In the following detailed description, numerous specific details are setforth to provide a full understanding of the subject technology. Itshould be understood that the subject technology may be practicedwithout some of these specific details. In other instances, well-knownstructures and techniques have not been shown in detail so as not toobscure the subject technology.

While the present description sets forth specific details of variousembodiments, it will be appreciated that the description is illustrativeonly and should not be construed in any way as limiting. It iscontemplated that although particular embodiments of the presentinventions may be disclosed or shown in particular contexts, suchembodiments can be used in a variety of endoluminal applications.Various applications of such embodiments and modifications thereto,which may occur to those who are skilled in the art, are alsoencompassed by the general concepts described herein. Catheter-basedtherapy can include the transvascular injection of drug and/or embolicagents directly into or near the tumor vasculature using a catheter ormicrocatheter. Embolization therapy causes a shutdown of blood flow and,when the drug or other therapeutic is present, simultaneous release ofhigh concentrations of the drug or other therapeutic. In someembodiments, a therapeutic material is delivered to a region near, at orcontaining a cancerous or hyperplasia tissue using a device and methodas described herein, wherein an embolic material is not also deliveredto the region. In this embodiment, an implant can be deployed (e.g.,downstream of the region) prior to delivery of the therapeutic materialto the region thereby providing an increased concentration of thetherapeutic material within the region as compared to the concentrationof the therapeutic material within the region after delivery in theabsence of the implant deployed downstream of the region.

Some embodiments of the procedure, technique, and implant disclosedherein can enable a clinician, in one or a several clinical procedures,to occlude, dynamically control the flow through, or deploy a materialthrough an implant. For example, according to some embodiments disclosedherein, procedures, techniques, and implants are provided by which animplant can be deployed into a body lumen in order to provide targeteddelivery of a material, such as an embolic material, contrast agent, ortherapeutic agent such as a drug or nanoparticle. In some embodiments,the embolic material is a therapeutic agent. It shall be noted that eventhough some of the embodiments disclosed herein may refer to the use ofan embolic material, such embodiments can employ one or more materials,such as embolic materials, contrast agents, or drugs, including thosedisclosed herein and other acceptable materials.

In some embodiments, the therapeutic material released by the devicesdescribed herein is any therapeutic agent which is effective in treatinga cancer or malignancy or another disease characterized by abnormalcellular proliferation. A therapeutic or therapeutically effectivematerial is a material which produces a therapeutic response in asubject. The therapeutic material is effective, for example, in reducingthe size of a tumor, reducing the rate of growth of a tumor, activatingapoptosis of malignant cells within a tumor, preventing tumor growth,and/or preventing or reducing the rate of cellular proliferation. Insome embodiments, the therapeutic material is effective to reduce tumorsize by at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or95% of the size of the tumor prior to treatment. Examples of embolictherapeutics include but are not limited to chemotherapeutics, metalnanoparticles, radiosensitizers, blood substitutes carrying oxygen,photothermal agents, and radioembolics or combinations thereof and aredescribed in more detail below.

When used to treat a cancer, a therapeutically effective material is onewhich can cause or facilitate death (apoptosis) of the cancer or tumorcells, reduce the growth rate of the cancer or tumor cells, and/orprevent the growth or maintenance of cancer or tumor cells. In otherembodiments. Therapeutically effective amounts are readily ascertainedby one of ordinary skill in the art and can be demonstrated in vitroand/or in vivo. In some embodiments, the subject is a mammal. In otherembodiments, the subject can be but is not limited to a primate, ahuman, a mouse, a rat, a pig or a dog.

Accordingly, in one aspect of the disclosure, a method for treating ahyperplasia disorder or a cancer is provided comprising delivery to aregion at, within or near the cancerous tissues, a therapeutic materialusing the devices and methods described herein. In some embodiments, thecancer comprises a liver cancer, a pancreatic cancer, a leukemia, alymphatic cancer, a brain cancer, a head and neck cancer, a lung cancer,a breast cancer, a thyroid cancer, a prostate cancer, a stomach cancer,an esophageal cancer, a colon cancer, a rectal cancer, a testicularcancer, a bladder cancer, a cervical cancer, an ovarian cancer or a skincancer. Accordingly, in some embodiments, the method comprisesadministering to a subject suffering from or diagnosed with ahyperplasia disorder or cancer a therapeutic material which is effectivein treating the hyperplasia disorder or cancer.

Therapeutic and/or embolic materials which can be delivered to a subjectin need thereof using the devices and methods disclosed herein includebut are not limited to nanoparticles, radiosensitizers, bloodsubstitutes that carry increased oxygen, photothermal agents,radioembolics and chemotherapeutic agents or a combination thereof.Therapeutically effective agents function by essentially killing tumorcells, but can also affect normal cells in a subject's body, leading toadverse side effects. Accordingly, by using the devices and methodsdescribed herein, localized delivery of therapeutic agents or materialsto a site at or near a cancerous tissue can significantly limit adverseside effects while also increasing potency of the therapeutic materialas localized concentrations of the material are greater at the site ofthe diseased tissue as compared to concentrations obtained by, e.g.,intravenous or peritoneal administration.

Nanoparticles used with the present devices and methods arebiocompatible particles designed to have specific physical propertiessuch as high absorptivity for specific wavelengths. When an energysource such as a laser producing nonionizing electromagnetic radiationis applied, conversion to heat energy occurs in metal nanoparticlesowing to electron excitation and relaxation. Furthermore, lasers can bespecifically tuned to the surface plasmon resonance (SPR) frequency ofnanoparticles, which varies with the size, shape and composition of thenanoparticle. Much research has used gold nanoshells, particles with 100nm silica cores and a 15 nm gold coating, which shifts the resonancepeak to the near infrared region (650-950 nm) where blood and tissue aremaximally transmissive. Accordingly, exposure of these nanoshells ornanoparticles to a near infrared laser results in increased temperatureof the particle and surrounding cell and tissue, facilitating andaccelerating death of the cancer cell.

Nanoparticles for use herein contain one or more metals such as but notlimited to gold, platinum, silver, titanium, palladium molybdenum,chromium, lead, iron, cobalt, nickel, zinc, tungsten, iridium, osmium,manganese, aluminum, tantalum, bismus, or any combination thereof.Nanoparticles for therapeutic use as described herein can also be madeof alloys as known to the skilled artisan including single-elementoxides, multi-element oxides and compounds. Included are gold alloyssuch as nanoparticles having gold and an iron oxide (Fe₂O₃ or Fe₃O₄)(e.g., Gheorghe et al., 2011, Nanoscale Res Lett, 6:554-565, theentirety of which is incorporated herein by reference). Thenanoparticles are generally bound to a targeting moiety such as anantibody or peptide (such as an antibody or peptide that specificallybinds to a cell-surface cancer antigen), a drug or prodrug, athermophilic enzyme or a polyethylene glycol (PEG) or PEG derivative.

Once a therapeutic material comprising the nanoparticles is delivered tothe tumor site through catheterization as described herein, thenanoparticles can be taken up by and accumulate in the diseased cellsand enhance effects of radiation as probable photon and electroninteraction increases. In some embodiments, after delivery of thenanoparticles to the targeted region comprising the cancerous cells, thesubject is administered x-radiation externally in the region of thecancer. In other embodiments, described in more detail below, one ormore optical fibers are used which deliver infrared light having awavelength of about 850 nm to 1550 nm or of about 850 nm, 1300 nm, or1550 nm. In still other embodiments, the optical fiber(s) deliversnear-infrared light having a wavelength of about 650 nm to 950 nm.Accordingly, in some embodiments, the lumen 570 encases an opticalfiber(s) as described herein or as readily known to the ordinarilyskilled artisan. In some embodiments, the one or more optical fibers arein independent conduits within the device or can be coupled to thedevice to the catheter of the device. In some other embodiments, theoptical fiber(s) are in a communal lumen wherein the fiber(s) are in alumen of the catheter which also delivers the therapeutic material. Insome embodiments, the optical fiber runs the length of the catheter andis controlled by the deployment handle assembly. The distal end of theoptical fiber is located near, at or distal to the distal end of thecatheter to allow a user to deliver the electromagnetic radiation (e.g.,infrared or near-infrared light) to the targeted region after deliveryof therapeutic material (e.g., nanoparticles) as described herein. Insome embodiments, the optical fiber(s) is connected to a laser sourcewhich is located outside of the catheter and in collaboration withselected connection devices. The presence of the gold particles near orin the diseased tissue results in increased radiation damage to thecells such that the same level of tumor killing is achieved with lessradiation exposure to the patient. In other words, use of targeted goldnanoparticles can either reduce the amount of radiation needed,providing better patient safety, or increase the level of tumor killingwithout exposing the patient to more radiation.

The nanoparticles can be synthesized to have a diameter ranging fromabout 0.4 nm to 5000 nm, however, only nanoparticles of a size of about1 nm to 100 nm can be internalized by cells. Accordingly, nanoparticlesaccording to the present disclosure have a diameter of about 0.4 nm to1000 nm, 0.4 nm to 500 nm, 0.4 nm to 250 nm, 0.4 nm to 100 nm, 0.4 nm to75 nm, 0.4 nm to 50 nm, 25 nm to 75 nm, 40 nm to 50 nm, 0.4 nm to 25 nm,0.4 nm to 20 nm, 0.4 nm to 15 nm, 0.4 nm to 10 nm, 0.4 nm to 5 nm, 0.4nm to 4 nm, 0.4 nm to 3 nm, 0.4 nm to 2 nm, or 1 nm to 2 nm. Generationof gold nanoparticles is standard in the art or nanoparticles can bepurchased (e.g., Nanoprobes, Inc. (Yaphank, N.Y.)).

In some embodiments, the nanoparticles (e.g., gold nanoparticles) aretargeted to cancer cells by linking the nanoparticles to a pHlow-insertion peptide (see, e.g., Andreev et al., 2010, Mol Membr Biol,27:341-352; Sosunov et al., 2013, Proc Natl Acad Sci, 110:82-86; Antoshet al., 2015, Proc Natl Acad Sci, 112:5372-5376; the entireties of whichare incorporated herein by reference). A pH low-insertion peptide is amoderately hydrophobic peptide that can insert into membranes (e.g.,cellular membranes or liposome) at mild acidic pHs, and which locatethemselves at cell surfaces where the pH is lowest. As diseased tissuehas been shown to have an extracellular pH which is lower than incomparable normal tissue resulting from enhanced use of glycolysis andproduction of carbonic and lactic acids in the diseased cells. The pHlow-insertion peptide can be conjugated or linked to a nanoparticle by,for example, a disulfide bond between a cysteine residue at anN-terminal or C-terminal end of the peptide and a functional group onthe nanoparticle. In some embodiments, a monomaleimido gold nanoparticleis conjugated to a pH low-insertion peptide which contains a cysteineresidue via a disulfide-bond using methods known to the ordinarilyskilled artisan. In other embodiments, the pH low-insertion peptide hasan amino acid sequence selected from the group consisting of but notlimited to the peptide sequences described in Table 1 below.

TABLE 1  SEQ ID NO: pH Low-Insertion Peptide Sequence 1GEQNPIYWARYADWLFTTPLLLLDLALLVDADEG 2ACEQNPIYWARYWARYADWLFTTPLLLLDLALLVDADEGT 3GGEQNPIYWARYADWLFTTPLLLLDLALLVDADEGT 4ACEQNPIYWARYADWLFTTPLLLLDLALLVDADET 5AAEQNPIYWARYADWLFTTPLLLLDLALLVDADEGTCG 6GGEQNPIYWARYADWLFTTPLLLLDLALLVDADEGTCG 7ACEQNPIYWARYADWLFTTPLLLLDLALLVDADEGTG 8ACEQNPIYWARYADWLFTTPLLLLDLALLVDADEGT 9AKEQNPIYWARYADWLFTTPLLLLDLALLVDADEGT 10AAEQNPIYWARYADWLFTTPLLLLDLALLVDADEGTKCG 11AKEQNPIYWARYADWLFTTPLLLLDLALLVDADECT 12ACEQNPIYWARYANWLFTTPLLLLNLALLVDADEGTG 13ACEQNPIYWARYAKWLFTTPLLLLKLALLVDADEGTG 14GGEQNPIYWARYADWLFTTPLLLLDLALLVNANQGT 15AAEQNPIYWARYADWLFTTPLLLLALALLVDADEGT 16AAEQNPIYWARYAAWLFTTPLLLLDLALLVDADEGT 17AAEQNPIYWARYADWLFTTALLLLDLALLVDADEGT 18AAEQNPIYWARYADWLFTTPLLLLELALLVDADEGT 19AAEQNPIYWARYAEWLFTTPLLLLDLALLVDADEGT 20AAEQNPIIYWARYADWLFTDLPLLLLDLLALLVDADEGT 21GEQNPIYWAQYADWLFTTPLLLLDLALLVDADEGTCG 22GGEQNPIYWARYADWLFTTPLLLDLLALLVDADEGTCG 23GGEQNPIYWARYADWLFTTPLLLLLDALLVDADEGTCG 24GGEQNPIYWARYDAWLFTTPLLLLDLALLVDADEGTCG 25GGEQNPIYWARYAWDLFTTPLLLLDLALLVDADEGTCG 26AAEQNPIYWARYADWLFTTGLLLLDLALLVDADEGT 27DDDEDNPIYWARYADWLFTTPLLLLHGALLVDADECT 28DDDEDNPIYWARYAHWLFTTPLLLLHGALLVDADEGCT 29DDDEDNPIYWARYAHWLFTTPLLLLHGALLVNADECT 30DDDEDNPIYWARYAHWLFTTPLLLLHGALLVNANECT 31AEQNPIYWARYADFLFTTPLLLLDLALLVDADET 32AEQNPIYFARYADWLFTTPLLLLDLALLVDADEGT 33AEQNPIYFARYADFLFTTPLLLLDLALLWDADET 34 AKEDQNPYWARYADWLFTTPLLLLDLALLVDG35 ACEDQNPYWARYADWLFTTPLLLLDLALLVDG 36 AEDQNPYWARYADWLFTTPLLLLDLALLVDCG37 AEDQNPYWARYADWLFTTPLLLLELALLVECG 38 AKEDQNPYWRAYADLFTPLTLLDLLALWDG 39ACEDQNPYWRAYADLFTPLTLLDLLALWDG 40 AKEDQNDPYWARYADWLFTTPLLLLDLALLVG 41TEDADVLLALDLLLLPTTFLWDAYRAWYPNQECA 42 AEQNPIYW ARYADWLFTTPL 43AEQNPIYW ARYADWLFTTPCL 44 ACEQNPIYW ARYADWLFTTPL 45 AEQNPIYFARYADWLFTTPL46 KEDQNPWARYADLLFPTTLAW 47 ACEDQNPWARYADLLFPTTLAW 48ACEDQNPWARYADWLFPTTLLLLD 49 ACEEQNPWARYAELLFPTTLAW 50ACEEQNPWARYAEWLFPTTLLLLE 51 ACEEQNPWARYLEWLFPTETLLLEL 52AEQNPIYWARYADWLFTTPLLLLDLALLVDADEGCT

In some embodiments, the gold nanoparticle conjugated to the pHlow-insertion peptide is delivered to a diseased region using thedevices and methods as described herein. In an alternative embodiment, aliposome comprising the gold nanoparticle conjugated to the pHlow-insertion peptide (e.g., US 2015/0086617, the entirety of which isincorporated herein by reference) is delivered to the diseased regionusing the devices and methods as described herein.

A metal nanoparticle such as a gold or gold alloy nanoparticle (e.g.,gold with iron oxide) can be attached to an antibody wherein theantibody is one which specifically binds to a tumor antigen. It isunderstood that a tumor antigen is a protein which is expressed on thesurface of a tumor cell but it not expressed on a normal cell of thesame tissue, is minimally expressed on the normal cell or is expressedon the normal cell at a level which is at least 10-fold, 100-fold or1000-fold less than its expression on the tumor cell as determined byprotein or mRNA quantitation techniques known in the art. The antibodycan be a full-length antibody having both heavy and light chains or afragment thereof which includes the antigen-binding portion of anantibody. Accordingly, the nanoparticle can be linked to an antibodyfragment which can be, for example: (i) a Fab fragment, a monovalentfragment consisting of the V_(L), V_(H), C_(L) and C_(H1) domains; (ii)a F(ab′)₂ fragment, a bivalent fragment comprising two Fab fragmentslinked by a disulfide bridge at the hinge region; (iii) a Fd fragmentconsisting of the V_(H) and C_(H1) domains; (iv) a Fv fragmentconsisting of the V_(L) and V_(H) domains of a single arm of anantibody, (v) a dAb fragment, which consists of a V_(H) domain; (vi) asingle chain Fv (scFv) in which the V_(L) and V_(H) regions pair to formmonovalent molecules, or (vii) an isolated complementarily determiningregion (CDR), all of which are well known in the art.

In some embodiments, the gold/iron oxide alloy nanoparticle which isdelivered to a tumor cell, for example through its association with anantibody, antibody fragment or pH low-insertion peptide, is exposed tonear-infrared light waves using a laser. The light penetrates deep intothe tissue, heating the nanoparticles to about 100° F., 110° F., 115° F.or 120° F. or to at least 100° F., 110° F., 115° F. or 120° F., therebykilling the cells. Accordingly, in some embodiments, a method fortreating a cancer or tumor is provided comprising delivering to a targetregion at, near or having the cancer or tumor cells a therapeuticmaterial using the devices and methods described herein. In someembodiments, the therapeutic material contains a metal nanoparticle. Inother embodiments, the metal nanoparticle is gold or a gold alloy. Inyet other embodiments, the gold alloy is a gold-iron oxide alloy. Instill other embodiments, the method further comprises administeringinfrared or near-infrared light to the therapeutic material afterdelivery wherein the administering light is through an optical fiberwhich is encased within and extends through the catheter of the deliverydevice as described herein.

Another therapeutic material which can be delivered using the devicesand methods described herein is referred to as radioembolics.Radioembolics are embolic materials which are associated with or linkedto a radioactive agent such at ⁹⁰Y. For example, glass microsphereshaving a diameter of about 40 μm to 50 μm are impregnated with ⁹⁰Y.Accordingly, a therapeutic material comprising the ⁹⁰Y microsphere isdelivered to a region at or near the cancer using the devices andmethods disclosed herein, providing localized radiation treatment andkilling of the tumor cells.

In some embodiments, the therapeutic material delivered to the cancerousregion comprises a radiosensitizer. A radiosensitizer is a drug thatmakes tumor cells more sensitive to radiation therapy. One example of aradiosensitizer is oxygen, increasing the effectiveness of a given doseof radiation by forming DNA-damaging free radicals. Accordingly, in someembodiments, the therapeutic material comprises a blood substitute. Theblood substitute can comprise an oxygen-carrying blood substitutepreparation containing an oxygen-carrying substance capable ofreversibly binding and releasing oxygen in vivo. The blood substitutemay include substances of native origin such as those derived from redblood cells. Alternatively, the blood substitute can contain, forexample, liposome-encapsulated hemoglobin, porphyrin metalcomplex-albumin complex, polyethylene glycol (PEG)-modified porphyrinmetal complex-albumin conjugate, hemoglobin, intra- and intermolecularlycrosslinked hemoglobin, polymerized hemoglobin, PEG-modified polymerizedhemoglobin, and a mixture thereof. In other embodiments, theradiosensitizer is selected from the group consisting of axol,nisonidazole, metronidazole, etanidazole, 5-fluorouracil, texaphyrin,C225 (an anti-EGFR monoclonal antibody), and cyclooxygenase-2 inhibitor.The radiosensitizer may also be a prodrug (e.g., precursor substancesthat are converted into an active form in the body) of any of the abovedescribed radiosensitizers.

Tumor cells in a hypoxic environment may be as much as 2 to 3 times moreresistant to radiation damage than those in a normal oxygen environment.Accordingly, in some embodiments a method for treating a cancer orhyperplasia disorder is provided comprising delivering a therapeuticmaterial to a cancerous tissue in a subject through a catheter accordingto the devices and methods described herein wherein the therapeuticmaterial comprises a radiosensitizer, then exposing the diseased orcancerous tissue to ionizing radiation. In some embodiments, theionizing radiation is x-irradiation or γ-irradiation. In otherembodiments, the x-ray is externally administered to the subject. In yetother embodiments, the ionizing radiation is provided by delivering tothe cancerous tissue a ⁹⁰Y microsphere through the catheter.

Chemotherapeutic agents can also be delivered to a cancerous region in asubject using the devices and methods described herein. Thechemotherapeutic used as well as the dose used is readily determined bythe person having ordinary skill in the art. Accordingly, in someembodiments, a method for treating a cancer or hyperplasia disorder in asubject is provided comprising delivering a therapeutic material to acancerous tissue in the subject through a catheter according to themethods described herein wherein the therapeutic material comprises achemotherapeutic agent, wherein the chemotherapeutic agent is effectivein treating the cancer.

In some embodiments, the therapeutic material comprises a photothermalagent. A photothermal agent is a moiety which, when exposed to lightsuch as infrared or near-infrared light via laser therapy using anoptical fiber, rises in temperature thereby increasing the temperatureof the microenvironment in which the photothermal agent is localized.Accordingly, in some embodiments, a method for treating a cancer orhyperplasia disorder in a subject is provided comprising delivering atherapeutic material to a cancerous tissue in the subject through acatheter according to the methods described herein wherein thetherapeutic material comprises a photothermal agent, wherein thephotothermal agent generates a rise in temperature in the canceroustissue to which it is delivered when the photothermal agent is exposedto infrared or near-infrared light. One example of a photothermal agentis a nanoparticle comprised of gold or a gold iron-oxide alloy and whichis targeted to the cancerous region as described herein.

In some embodiments, methods and implants are provided in which aclinician can deposit embolic or other therapeutic material as describedherein into a target area downstream of an implanted shunt whilepreventing upstream flow or backflow of the particles away from thetarget area.

In some embodiments, an implant can be expanded into apposition with aluminal wall to at least partially occlude flow through the lumen, andembolic or other therapeutic material can be released through anaperture or valve component of the implant, thereby isolating the flowof embolic material into the target region. The valve component cancomprise a one-way valve. Such procedures, techniques, and implants canbe used to induce infarction of tumors, arteries, or other target bodyregions.

Further, in accordance with some embodiments, a clinician can place oneor more implants into the vasculature and use of an implant tofacilitate the delivery of a material, such as an embolic or othertherapeutic material, to a target region within the body.

For example, a clinician can advance an implant to a location upstreamof specific arteries and/or a target structure fed by the arteries. Atleast a portion of the implant can be expanded into apposition with thevessel wall, thereby reducing and/or eliminating any anterograde bloodflow past the implant. Thereafter, a material can be passed through avalve component or aperture of the implant in order to pass the materialtoward the target region. Such embodiments advantageously enhance orincrease the concentration of material delivered to the arteries andtarget structure. Further, in some embodiments, a distal implant can bereleased at a location immediately distal to the target region such thatthe distal implant prevents or mitigates any downstream migration of thematerial toward a downstream section of the vessel.

Some embodiments of the flow regulating implant can comprise a generallytubular member. In some embodiments, the tubular member can furthercomprise a graft, cover, or other material attached to a frame. Someimplants that can be used in some embodiments are disclosed inapplicant's co-pending U.S. patent application Ser. No. 12/906,933,filed on Oct. 18, 2010, Ser. No. 13/828,974, filed on Mar. 14, 2013, and61/835,406, filed on Jun. 14, 2013, titled “Implantable Luminal Devicesand Methods,” the entireties of which are incorporated herein byreference.

FIGS. 1 and 2 illustrate embodiments of an implant carrier assembly. Asshown in FIGS. 1 and 2, the implant carrier assembly 500, 500′ cancomprise a catheter 510 having a lumen that extends between a proximalportion 512 and a distal portion 514 of the catheter. The catheter 510can also comprise an engagement section 516, which can be located alonga distal portion of the catheter 510, configured to engage and/orrestrain an implant positioned therealong. Thus, the implant can besupported, engaged, or restrained along an exterior surface of thecatheter. The catheter 510 can define a length from about 50 cm to about200 cm, from about 70 cm to about 160 cm, or in some embodiments, about120 cm, with a working length of from about 85 cm to about 140 cm, fromabout 95 cm to about 130 cm. In accordance with some embodiments, thetotal length of the implant carrier assembly (with handle) can be about117 cm, with a working length of 97 cm.

The catheter 510 can be configured to move within a guide sheath whenadvancing the assembly 500, 500′ into a patient for treatment. Theproximal portion 512 of the catheter 510 can be configured to berelatively stiff in order to enhance the pushability of the catheter 510through the guide sheath. Further, the distal portion 514 can berelatively flexible in order to improve the maneuverability andtrackability of the catheter 510 as it is advanced through the guidesheath.

The assembly 500, 500′ can also comprise an implant or device 520 loadedon the engagement section 516. The implant 520 can be supported on theengagement section 516 of the catheter 510. Further, the assembly 500,500′ can also comprise a deployment handle assembly 530, 530′ attachedto the catheter proximal portion 512. The deployment handle 530 shown inFIG. 1 includes two pull members 532, whereas the deployment handle 530′shown in FIG. 1 includes a single pull member 532′. As discussed furtherherein and in co-pending U.S. patent application Ser. No. 14/044,794,filed Oct. 2, 2013, the entirety of which is incorporated herein byreference, the pull members 532, 532′ can be used to release the implant520 from engagement with the engagement section 516 of the catheter 510.In some embodiments, both deployment handles 530, 530′ can be used torelease distal and proximal portions of the implant 520. However, thedeployment handle 530 can be configured to provide dedicated pullmembers 532 for releasing each of the distal and proximal portions ofthe implant 520. In contrast, the deployment handle 530′ can beconfigured to provide a single pull member 532′ that can be, forexample, moved a first distance to release the distal portion of theimplant 520 and pulled a second distance to release the proximal portionof the implant 520. Either embodiment can be used in performing themethods and procedures disclosed herein.

Other features and characteristics of the assembly 500, 500′ can beprovided such as those disclosed in co-pending U.S. patent applicationSer. No. 14/044,794, filed Oct. 2, 2013, the entirety of which isincorporated herein by reference.

As shown in FIGS. 3-4, the implant 520 can be supported on theengagement section 516 of the catheter 510. The implant 520 can compriseone or more apertures or valve components that can be actuated to permitflow of a material, such as an embolic or other therapeutic material,contrast agent, or drug, through the implant 520. The implant 520 cancomprise a plurality of components, such as one or more supportcomponents 540, a valve component 542, and/or a cover member 544. Thecover member 544 can comprise an aperture through which the material canbe passed. In embodiments using a valve component 542, the valvecomponent 542 can be coupled to the support component 540 and/or covermember 544 and can permit flow of the material therethrough.

FIGS. 5A-5B illustrate aspects of an engagement system between thecatheter 510, the support component 540, and at least one engagementcomponent 546 a, 546 b. As noted above, when using a single pull member532′, a single engagement component 546 can be used to engage andrelease proximal and distal portions 534, 536 of the support component540. Further, when using to pull members 532, two engagement components546 a, 546 b can be used to engage and release the proximal and distalportions 534, 536 of the support component 540. Various aspects of suchembodiments are disclosed in co-pending U.S. patent application Ser. No.14/044,794, filed Oct. 2, 2013, the entirety of which is incorporatedherein by reference. Thus, the implant 520 can be delivered usingvarious embodiments of the carrier assembly 500, 500′.

In accordance with some embodiments, the engagement system can beconfigured such that the support component comprises one or moreapertures that extend through one or more portions thereof to facilitateengagement with at least one engagement component when the supportcomponent is coupled to the catheter. For example, the engagementcomponent can extend through the lumen of the catheter adjacent anaperture, notch, or slot of the catheter and pass through an aperture ofa distal end portion of the support component in order to engage thedistal end portion and secure the distal end portion relative to theaperture, notch, or slot of the catheter. The aperture can extendthrough the support component at an end portion or other locationbetween the end portions, such as a midportion thereof.

Further, the support component can be coupled to the catheter with theengaged portion of the support component extending through the aperture,notch, or slot of the catheter. Advantageously, the engagement betweenthe support component and the engagement component within the catheterlumen can reduce the profile of the carrier assembly, thereby permittingthe assembly to be compatible with small gauge catheters, such as sizesbetween about 3 Fr and about 8 Fr, about 4 Fr and about 7 Fr, or about 5Fr and about 6 Fr. However, in some embodiments, the engagementcomponent can extend radially external to or outwardly from the catheterlumen to engage the portion of the support component outside of thecatheter lumen and still provide compatibility with small gaugecatheters.

In accordance with some embodiments, the implant carrier assembly can beconfigured to comprise at least one engagement member that extends atleast partially through the catheter lumen. The engagement member canengage at least a portion of, and in some embodiments, one or both theproximal and distal sections of the support component. The engagementmember can comprise a wire. However, in some embodiments, the engagementmember can comprise a plug or other structure that can interact with oneor both of the proximal or distal sections of the support component.

In some embodiments, the engagement member can be actuatable orcontrollable using a handle assembly, as discussed further below.

For example, an engagement section of the catheter can be configured tofacilitate engagement between the support component and the engagementmember extending from the handle assembly. In some embodiments, theengagement member can be selectively actuated or withdrawn in order torelease engagement between the support component and the engagementmember. The movement of the engagement member can be configured to be aproximal withdrawal of the engagement member. However, the engagementmember can also be configured such that disengagement occurs when theengagement member is distally advanced (such as when a proximallyoriented hook or segment of the engagement member engages with thesupport component). Indeed, the engagement member can be moved a firstdistance (whether proximally or distally) in order to release ordisengage with one of the proximal or distal sections of the supportcomponent. Further, the engagement member can be moved a seconddistance, greater than the first distance (whether proximally ordistally) in order to release or disengage with the other one of theproximal or distal sections of the support component.

Further, in some embodiments, the engagement section of the catheter canfacilitate engagement between the implant and two or more engagementmembers extending from the handle assembly. Although the engagementmember is illustrated as extending between the proximal and distalsections of the support component, the engagement member can engage oneof the proximal or distal sections while a second engagement member canbe used to engage the other of the proximal or distal sections.

For example, the catheter can comprise an engagement section and alumen. The assembly can comprise an implant or support componentsupported on the engagement section. In some embodiments, the lumenhouses an optical fiber, described in more detail below, which extendsthrough the length of the lumen. In some embodiments, the catheter ismated to or over-molded onto the optical fiber. Further, the assemblycan comprise a first engagement member and a second engagement member546 a, 546 b configured to engage with the support component, as shownin FIG. 5B. As shown in FIG. 5A, a proximal portion of the engagementmember 546 b can engage a proximal portion of support component and adistal portion of the engagement member 546 a can engage with a distalportion of the support component.

Accordingly, in embodiments that comprise two engagement members, theengagement members can be actuated independently of each other in orderto control the release of the respective proximal or distal sections ofthe support component or implant. Additionally, in some embodiments, theoptical fiber can be actuated and controlled independently of theengagement members and the catheter in order to control the position ofthe distal end of the optical fiber and to control release ofelectromagnetic radiation from the optical fiber.

Additionally, some embodiments can be configured such that an engagementmember extends through the catheter lumen and between at least one ofthe proximal or distal sections of the support component and the wall ofthe catheter. For example, the engagement member can be disposedradially between the proximal or distal section of the support componentand the wall of the catheter.

For example, FIG. 5B illustrates the configuration of the catheter andthe aperture, notch, or slot in relation to the engagement member andthe proximal section of the support component. As shown, the proximalsection can sit within the aperture and provide enough clearance betweenthe proximal section and wall or the inner surface of the wall such thatthe engagement member can be positioned intermediate the wall and theproximal section. As also shown, the proximal section can extend acrossthe entire diameter of the lumen in a transverse direction. However, theproximal and/or distal sections can also be configured to extend acrossthe lumen less than a diameter of the lumen (whether in the transversedirection or in a radial direction).

Accordingly, the engagement member can secure the proximal sectionwithin the aperture to prevent movement of the proximal section in anaxial direction (shown in FIG. 5A) and/or a radial direction (shown inFIG. 5B). In some embodiments, the support component can be a resilientor self-expanding support component, such that the proximal section willtend to expand or move out of the aperture without the presence of theengagement member. Thus, when the engagement member is in place betweenthe proximal section and the wall of the catheter, the proximal sectioncan be retained or engaged within the aperture. However, when theengagement member is removed from between the catheter and the proximalsection of the support component, the proximal section of the supportcomponent will no longer be constrained and can therefore expand out ofthe aperture, notch, or slot.

The engagement between the proximal section, the engagement member, andthe aperture can also be present at the distal end of the supportcomponent, although it will not be discussed further herein. However, asnoted, some embodiments can be implemented in which a single end of thesupport component is retained within an aperture or otherwise engaged bythe engagement member.

In addition to FIGS. 5A-5B, FIGS. 6A-6E illustrate additional aspects ofsome embodiments of an engagement system. FIG. 6A illustrates a supportcomponent 540′ having a proximal end region 541 that comprises anaperture 543 extending therethrough. The aperture 543 can be configuredto receive at least one engagement component therethrough. For example,in FIG. 6A, the engagement component 546 b passes through the aperture543 of the proximal end region 541, thus securing the proximal endregion 541 relative to the aperture, the notch, or slot 539 of thecatheter 510. In this manner, the proximal end region 541 can beradially secured (such that the proximal end region 541 does notradially expand out of the slot 539) and circumferentially or laterallysecured (such that the proximal end region 541 does not slide out of theslot 539) relative to the catheter 510.

The proximal end region 541 can comprise a flattened portion, asillustrated in the cross-sectional view of FIG. 6B. However, theproximal end region 541 can also extend along an arcuate path withouthaving a discrete flattened portion.

FIG. 6B (and as generally shown in the embodiment of FIGS. 5A-5B) alsoillustrates that the slot 539 formed in the catheter 510 can, in someembodiments, be defined by a line segment or chord 537 extending throughthe catheter lumen 517. The line segment or chord 537 can intersect withthe circumference of the catheter 510. The line segment 537 can be adiameter of a circular cross-section, but need not be a diameter and canbe a chord intersecting the circumference. The line segment 537 candefine a base or bottom of the slot 539. The orientation or spacing ofthe line segment 537 from an outer circumference of the catheter 510 candefine a slot depth. The slot depth can be measured as the distance fromthe line segment to the outermost point along the circumference of thecatheter 510. As noted below, the slot can have a depth that extendsbetween about ⅕ and about ⅔ of the catheter outer diameter, such asabout ¼, ⅓, or ½ of the catheter outer diameter.

Referring still to FIG. 6B (and generally to FIG. 5B), the slot 539 canextend only partially into the catheter lumen 517, such that the lumen517 provides sufficient space for embolic and/or therapeutic material topass therethrough. When viewed in cross-section, the line segment candivide the lumen 517 into first and second portions. For example, theengagement component 543 and the proximal end region 541 can bepositioned within a first portion of the lumen 517. A second portion ofthe lumen 517 can be a clear-through portion that allows material suchas embolic or therapeutic material to be urged therethrough. The firstportion of the lumen 517 in some embodiments can provide a path throughwhich an optical fiber is passed.

Further, the proximal end region 541 can comprise at least one apertureextending therethrough. In some embodiments, the aperture can extendthrough the proximal end region in a direction transverse to alongitudinal axis of the support component. For example, in someembodiments, the proximal end region can be flat, and the aperture canextend through the flat proximal end region, as illustrated in FIGS.6A-6E. However, the aperture can also extend through the proximal endregion in a direction substantially parallel relative to a longitudinalaxis of the support component. In such embodiments, the proximal endregion can have a flat, square, rectangular, and/or twisted shape.According to some embodiments, the proximal end region 541 can bedeflectable in order to facilitate placement of the proximal end region541 into the slot 539 of the catheter 510.

The proximal end region 541 can define a width that is about equal to awidth of the support component 540′. Thus, in some embodiments, thesupport component 540′ may not have a tapering width in the proximal endregion 541. However, the support component 540′ can also taper toward alarger or smaller width in the proximal end region 541. For example, alarger width in the proximal end region 541 can facilitate theaccommodation of the aperture 543 thereat. However, non-tapering orother tapering embodiments of the proximal end region 541 can define awidth sufficient to accommodate the aperture 543 thereat.

In some embodiments, the width of the proximal end region 541 can be atleast about two times the width, size, or diameter of the aperture 543.However, in other embodiments, the width of the proximal end region 541can be three, four, five, or more times the width, size, or diameter ofthe aperture 543.

Some embodiments can also be configured such that the support componentand the cover member cooperatively substantially seal the slot of thecatheter lumen. FIGS. 6C-6E illustrate side, cross-sectional views ofthe embodiments of the catheter that can be used to couple theengagement component and the support component. According to someembodiments, the aperture, notch, or slot of the catheter can have aV-shape. However, the slot can comprise a slanted configuration and/orU-shaped configured to reduce and/or eliminate leakage of material fromthe slot when material is urged through the catheter lumen fordeposition into the body lumen.

FIGS. 6C-6D illustrate slots 539 a, 539 b formed in the catheter 510,which are slanted or extend transversely relative to a plane that isperpendicular relative to the longitudinal axis of the catheter 510.FIG. 6E illustrate a slot 539 c formed in the catheter 510, whichextends substantially within a plane that is perpendicular relative tothe longitudinal axis of the catheter 510.

In accordance with some embodiments, the slots 539 a, 539 b, 539 c canhave proximal and distal faces 513, 515. The proximal and distal faces513, 515 can extend in respective planes. In some embodiments, theproximal and distal faces 513, 515 can be defined by edges of thecatheter through which the slot is cut. The proximal and distal faces513, 515 (or the planes through which they extend) can be substantiallyparallel relative to each other (whereas the slot 539 of FIG. 6Aillustrates proximal and distal faces (or the planes through which theyextend) that are oriented transverse relative to each other). Theproximal and distal faces 513, 515 (or the planes through which theyextend) can be oriented substantially perpendicular relative to alongitudinal axis of the catheter. Further, in some embodiments, theproximal and distal faces 513, 515 (or the planes through which theyextend) can be obliquely oriented relative to a longitudinal axis of thecatheter.

As illustrated in FIG. 6C, the slot 539 a can be configured such thatthe proximal and distal faces 513 a, 515 a have a forward slant ororientation. For example, the slot 539 a or the proximal and distalfaces 513 a, 515 a can have a slope or taper that converges toward thelongitudinal axis of the catheter 510 in a direction away from asupporting area 511 of the catheter 510. Thus, the proximal end portion541 can be inserted into the slot 539 a at an angle relative to thelongitudinal axis of the catheter 510 and, referring to the orientationillustrated in FIG. 6C, turned counterclockwise to an angled orientationin order to insert the proximal end portion 540 into the slot 539 a.

The slot 539 b of FIG. 6D can be configured such that the proximal anddistal faces 513 b, 515 b have a reverse slant or orientation. Forexample, the slot 539 b or the proximal and distal faces 513 b, 515 bcan have a slope or taper that converges toward the longitudinal axis ofthe catheter 510 in a direction toward or into a supporting area 511 ofthe catheter 510. Thus, the proximal end portion 541 can be insertedinto the slot 539 b at an angle relative to the longitudinal axis of thecatheter 510 and, referring to the orientation illustrated in FIG. 6D,turned clockwise to an angled orientation in order to insert theproximal end portion 540 into the slot 539 b.

Further, as illustrated in FIG. 6E, the slot 539 c or proximal anddistal faces 513 c, 515 c can extend generally perpendicular relative tothe longitudinal axis of the catheter 510. Thus, the proximal endportion 541 can be inserted into the slot 539 c at a substantiallyperpendicular angle relative to the longitudinal axis of the catheter510 and, referring to the orientation illustrated in FIG. 6E, turnedclockwise or counterclockwise to an angled orientation in order toinsert the proximal end portion 540 into the slot 539 a.

Advantageously, the slots 539 a, 539 b, 539 c each are configured suchthat the proximal and distal faces of the slots 539 a, 539 b, 539 cclosely approximate the thickness of the proximal end portion 541 andthe membrane 520 wrapped around the proximal end portion 541 wheninserted into the slot. Accordingly, in embodiments of the catheter thatdo not comprise a dedicated or separate lumen for passage of material,the material passing through the catheter lumen 517 will not tend toleak from or exit the slot of the catheter lumen 517.

For example, the slots 539 a, 539 b, 539 c can define a slot width,between the proximal and distal faces, that is between about 0.004inches and about 0.012 inches. Further, the slot width can be betweenabout 0.005 inches and about 0.010 inches. Furthermore, the slot widthcan be between about 0.006 inches and about 0.008 inches, or about 0.007inches. As shown in FIG. 6A, the slot may be tapered (have a trapezoidalshape, when viewed in a side view along the longitudinal axis of thecatheter) with a wider end positioned toward the outer contour of thecatheter. Further, as shown in FIGS. 6C-6E, the slot may be straight(have a rectangular or square shape, when viewed in a side view alongthe longitudinal axis of the catheter).

In some embodiments, the thickness of the distal end portion 541 of thesupport component 540 can be between about 0.002 inches and about 0.008inches. Further, the thickness of the distal end portion 541 can bebetween about 0.003 inches and about 0.006 inches. In some embodiments,the thickness of the distal end portion 541 can be about 0.004 inches.

Thus, with a cover member 520 having a thickness of between about 0.0005inches and about 0.006 inches, the distal end portion 541 and covermember 520 can fit into the slot with high dimensional accuracy in orderto reduce any gap in the slot wherethrough material can exit thecatheter lumen.

Additionally, the slots 539 a, 539 b, 539 c can define a slot depth ordimension indicative of the diametric or radial extent of the slot intoor through the catheter 510. The slot depth can be between about ⅕ andabout ⅔ of the catheter outer diameter, such as about ¼, ⅓, or ½ of thecatheter outer diameter. The slot depth can be at least ⅓, ½, ⅔, or ¾ ofthe width of the proximal end portion 541. For example, the slot depthcan be between about 0.004 inches and about 0.110 inches. Further, theslot depth can be between about 0.008 inches and about 0.090 inches. Theslot depth can be between about 0.010 inches and about 0.060 inches.Furthermore, the slot depth can be between about 0.014 inches and about0.040 inches. The slot depth can be or between about 0.018 inches andabout 0.030 inches. In some embodiments, the slot depth can be about0.020 inches, about 0.024 inches, or about 0.028 inches.

Further, the engagement component can have a diameter of between about0.001 inches and about 0.020 inches, between about 0.003 inches andabout 0.010 inches, or between about 0.004 inches and about 0.007inches, such as 0.005 inches.

The proximal end portion can define a width of between about 0.010inches and about 0.030 inches, between about 0.012 inches and about0.020 inches, between about 0.014 inches and about 0.018 inches, and insome embodiments, about 0.015 inches.

In some embodiments, the catheter lumen can have an inner diameter ofbetween about 0.010 inches and about 0.080 inches, between about 0.015inches and about 0.070 inches, between about 0.020 inches and about0.060 inches, between about 0.025 inches and about 0.050 inches, orbetween about 0.030 inches and about 0.040 inches.

Further, the catheter can have an outer diameter of between about 0.020inches and about 0.160 inches, between about 0.030 inches and about0.140 inches, between about 0.040 inches and about 0.120 inches, betweenabout 0.050 inches and about 0.100 inches, or between about 0.060 inchesand about 0.080 inches. In some embodiments, the catheter outer diameteris about 3 Fr, 4 Fr, 5 Fr, 6 Fr, 7 Fr, 8 Fr, 9 Fr, 10 Fr, 11 Fr, or 12Fr.

Thus, the slot depth can be configured such that the proximal endportion can be inserted into the slot and a sufficient width of theproximal end portion can be received within the slot to allow theaperture to be accessible to the engagement component extending withinthe catheter lumen.

Furthermore, although FIGS. 6C-6E illustrate embodiments of a singleslot, the catheter can be configured to comprise two or more slots thatcan be used to couple the support component thereto. One or both of thetwo or more slots be configured such as the slots illustrated byelements 539, 539 a, 539 b, or 539 c. Thus, the two or more slots can beidentical or different in size, shape, or orientation. Further, thecatheter can comprise a single or dual lumen structure. According tosome embodiments, the slot structures and embodiments illustrated inFIG. 6C-6E can be particularly advantageous for tending to reduce and/oreliminate leakage through the slots of a single lumen catheterstructure.

For any embodiment of the assembly and/or implant disclosed herein, theslot width, slot depth, catheter lumen inner diameter, catheter lumeninner diameter, engagement component diameter, aperture diameter,proximal end portion width, and proximal end portion thickness can beconfigured within any of the ranges disclosed herein.

In some embodiments, a portion of the catheter can be configured to movebeyond or through the distal portion of the implant in order toprecisely deliver a material into the lumen downstream of the implant.The implant distal portion (e.g., a valve component of the implant) andthe catheter distal tip can have a close fit, thus allowing material tobe injected into the lumen while avoiding dispersion or diffusion of thematerial upstream of the implant. For example, in some embodiments, theimplant proximal portion can be maintained engaged with the catheterwhile the implant distal portion is allowed to expand into contact withthe vessel wall. The expansion of the implant distal portion can causethe implant to foreshorten and thus cause the distal portion of thecatheter to move beyond or through the distal portion of the implant,whereafter material can be injected into the lumen, thus avoidingdispersion or diffusion of the material upstream of the implant.

However, in some embodiments, the implant distal portion can bemaintained engaged with the catheter while the implant proximal portionis allowed to expand into contact with the vessel wall, whereaftermaterial can be injected into the lumen, thus avoiding dispersion ordiffusion of the material upstream of the implant.

According to some embodiments, while a proximal or distal portion of theimplant is initially expanded with the other portion being maintainedengaged with the catheter, or after both portions of the implant areexpanded and released from the catheter, the catheter can be urgeddistally relative to the implant distal portion such that the catheterdistal tip extends beyond or through the implant distal portion.

In any of such embodiments, the deployment handle and its pull member(s)can be interconnected with the engagement component(s) to allow desiredactuation of the assembly and implant. When two pull members are used,the proximal pull member can be interconnected with the engagementcomponent that controls release of either the distal or proximal implantportion. Accordingly, some embodiments disclosed herein can allow aclinician to target specific regions and precisely control the flow anddispersion of the material.

In some embodiments, the material delivery device further comprises oneor more optical fibers. In some embodiments, when the implant devicefurther comprises an optical fiber, the deployment handle and one of itspull members can be interconnected with the optical fiber to allowdesired actuation of the fiber. The pull member which is interconnectedwith the optical fiber can be used to control the proximal and distalmovement of the distal end of the optical fiber to provideadministration of electromagnetic radiation near the target region afterdelivery of an embolic and/or therapeutic material. The deploymenthandle can further comprise an optic control element interconnected withthe optical fiber to control the wavelength and duration of lightprovided by the optical fiber. In some embodiments, the materialdelivery device is connected to a laser source which is located outsideof the catheter and in collaboration with the optical fiber. The lasersource, in some embodiments, provides infrared or near-infrared light.

For example, a carrier assembly can be configured such that anengagement component can be withdrawn from the assembly and replacedwith an optical fiber. This removal can occur after the portion of theimplant constrained by the withdrawn engagement component has beenreleased from the carrier assembly. Further, the pull member coupled tothe withdrawn engagement component can be entirely removed and separatedfrom the carrier assembly. However, the pull member can also bedecoupled from the withdrawn engagement component and coupled to aproximal end of the optical fiber and thereafter, the optical fiber canbe introduced into the carrier assembly and advanced distally to thetarget region. Moreover, in some embodiments, one or more of theengagement component can comprise or be made from an optical fiber.Thus, the “optical” engagement component can be used for not onlymechanical engagement but also for delivering light or energy to thetarget area. Such embodiments can incorporate any of the variousfeatures disclosed herein.

Referring now to FIGS. 7A-12B, various embodiments of the implant 520are illustrated in which the implant 520 comprises different valvecomponents.

FIGS. 7A-7B illustrate an implant 520 a having a valve component 542 athat comprises a flap structure 550 a. The flap structure 550 a canextend distally from the implant 520 a. The flap structure 550 a cancomprise one or more sections of material of a cover member 544 a. Insome embodiments, the flap structure 550 a can comprise at least anouter layer of the cover member 544 a. For example, the cover member 544a can comprise inner and outer sections 545 a, 545 b. The inner andouter sections 545 a, 545 b can at least partially envelop, enclose, orcover the support component 540.

In some embodiments, the cover member 544 a can comprise a tubularmembrane that is everted or inverted such that the outer section 545 bextends along an exterior of the support component 540 and the innersection 545 a extends along an interior of the support component 540.The cover member 544 a can be unitarily formed as an uncut, continuoustube or can comprise one or more longitudinal cuts or breaks such thatthe inner or outer sections 545 a, 545 b comprise one or more strips ofmaterial. The cover member 544 a and/or the implant 520 a can compriseadditional features such as those disclosed in co-pending U.S. patentapplication Ser. No. 14/044,794, filed Oct. 2, 2013, the entirety ofwhich is incorporated herein by reference.

As illustrated in FIG. 7A, in some embodiments, the inner section 545 acan comprise one or more strips of material that can be secured to thedistal end portion of the outer section 545 b using a mechanical,thermal, or chemical coupling. For example, a suture, adhesive, or tiecoupling 547 can be used to couple a strip of the inner section 545 awith the distal end portion of the outer section 545 b. In someembodiments, the flap structure 550 a can comprise the coupling 547;however, the coupling 547 can also be omitted from the flap structure550 a and implant 520 a.

In some embodiments, such as that illustrated in FIGS. 7A-7B, thecoupling 547 can secure only a portion of the inner or outer sections545 a, 545 b to each other. However, in some embodiments, the entireinner section 545 a can be secured to the entire outer section 545 b. Asshown in FIG. 7B, a distal portion 548 a of the implant 520 a can bereleased (using the engagement component 546 a) while a proximal portion549 a is maintained in engagement (using the engagement component 546b). As the distal portion 548 a expands and the implant 520 aforeshortens, the coupling 547 can be drawn proximally. At this point,in some embodiments of the methods or procedures disclosed herein, amaterial (e.g., embolic material, contrast agents, or therapeuticagents) can be passed through a delivery lumen 570 of the catheter 510(shown by arrows 571) into downstream vasculature 559 of the vessel 561(see FIGS. 7C-7D). However, the material can also be delivered after theproximal portion 549 a has been released. For example, the distal tip564 of the catheter 510 can then move distally beyond the distal portion548 a of the implant 520 a to provide a clear outflow pathway formaterial injected through the catheter 510.

The catheter can comprise a single or dual lumen structure incombination with any of the embodiments disclosed herein. FIGS. 7A-7Band 8A-8C illustrate a single lumen structure while FIGS. 9A-10Billustrate a dual lumen structure.

FIGS. 7C-7D illustrate the release, closing, and sealing of the valvecomponent 542 a in a lumen 561. These figures illustrate that the distalportions of the inner and outer sections 545 a, 545 b can be coupledtogether or closed on top of each other. For example, in someembodiments, the inner and outer sections 545 a, 545 b can be closedusing an adhesive material, which can be injected through the deliverylumen 570 of the catheter 510. Applicant has found that such embodimentscan advantageously provide a simple construction and at least apartially or fully complete seal to be achieved by adhering the innerand outer sections 545 a, 545 b to each other. FIG. 7C illustrates aninitial reflux or vacillation of the distal portions of the inner andouter sections 545 a, 545 b. During the back-and-forth movementrepresented in FIG. 7C, the distal portions can tend to adhere to eachother until being coupled to each other to close the lumen 561, therebypreventing flow therethrough, as shown in FIG. 7D. Thereafter, theimplant 520 a can at least partially or fully occlude the lumen 561.

In some embodiments, the procedure for expanding the cover component andsupport component of the implant can be modified such that the covercomponent expands into contact with the body lumen wall before thesupport component begins expanding. For example, the cover component canbe inflated by flushing the cover component with saline or othermaterial prior to releasing or permitting expansion of an end of thesupport component. This inflating step can be performed in operating anyof the implants that have a substantially closed end prior to expansionof the support component, which can permit an increase in fluid pressurewithin the cover component sufficient to inflate the cover component(see e.g., FIGS. 9A, 10A, 11A, and 12A that have valve components in asubstantially closed position prior to support component expansion; butsee e.g., FIG. 7A that has an open end formed by loose ends of the covercomponent). Further, as the cover component is inflated, the valvecomponent of the cover component can draw closer to the distal end ofthe catheter, which can provide various advantages and permit operationof the valve component using the distal end of the catheter, accordingto some embodiments.

Further, in some embodiments, the valve component can satisfy toseemingly opposite goals: (1) to provide eventual occlusion of thevessel and prevent or reduce reflux of material into a proximal portionof the vessel, and (2) to provide a secondary opportunity to return at alater time to provide a further treatment of the vessel withoutremoving, destroying, or otherwise damaging the valve component.

For example, in some embodiments, the valve component can comprise amesh or fibrous material. FIGS. 8A-8D illustrate an implant 520 b in acollapsed and expanded configurations. In FIG. 8A, the implant 520 bcomprises a cover member 544 b that at least partially encloses,envelops, or covers the support frame 540. The implant 520 b cancomprise distal and proximal portions 548 b, 549 b. The implant 520 bcan also comprise a mesh portion 550 b that is coupled to the distalportion 548 b of the implant 520 b.

The mesh portion 550 b can comprise a plurality of filaments, wovenePTFE strips or sutures, or other porous, biocompatible materials. Themesh portion 550 b can be coupled to the distal portion 548 b, such asby being coupled to the distal portion of the cover member 544 b. Asillustrated in FIGS. 8A-8D, the mesh portion 550 b can comprise a layerof material that is coupled to an outer surface of the cover member 544b along a distal portion of the cover member 544 b. The mesh portion 550b can be secured relative to the cover member 544 b using mechanical,thermal, or chemical bonding, such as adhesives. In some embodiments, africtional engagement can secure the mesh structure 550 b relative tothe cover member 544 b. For example, when the implant 520 b is expandedinto contact with the vessel wall, the mesh portion 550 b can be securedrelative to the implant 520 b and support structure 540 by virtue ofradial compressive force and frictional engagement against the vesselwall and the outer surface of the cover member 544 b.

The mesh portion 550 b can also be formed with the cover member 544 bfrom a single, continuous piece of material. For example, in someembodiments, the mesh portion 550 b can be formed as a tubular bodyhaving an open end and a closed end, opposite the open end, thatcomprises a plurality of pores, cells, apertures, perforations,incisions, windows, or other cuts to provide a substantially mesh-typeclosed end.

Thus, in some embodiments, the cover member 544 b can also be configuredas a material having a closed mesh end. In order to manufacture someembodiments of an implant, the tubular mesh body can be moved onto thedistal portion of the catheter 510, with the catheter 510 entering theopen end of the tubular body. The support component 540 can then bepositioned over a distal section of the tubular body and coupledrelative to the catheter 510. Further, a proximal section of the tubularbody, extending proximally of the support component 540, can thereafterbe everted over the support component 540 to at least partially coverthe support component 540. In some embodiments, the proximal section canbe at least partially coupled to a corresponding portion of the distalsection of the tubular body or mesh portion. Further, in someembodiments, the proximal section of the tubular body can extend fullydistally of the support component 540.

In use, the mesh portion 550 b can effectively protect against or tendto block proximal migration or reflux of material ejected into thedownstream vasculature 559 of the vessel 561. For example, although themesh portion 550 b can be sufficiently porous (e.g., have an averagepore size) that is greater than the size of particles of a materialpassing therethrough, thrombosis and/or the use of materials, such asglues, can tend to close the size of the pores of the mesh portion 550b. Accordingly, after the particles of the material have passed throughthe mesh portion 550 b, the mesh portion 550 b can tend to preventproximal migration or reflux. The mesh portion 550 b can thereby provideat least partial or full occlusion of the vessel 561.

Additionally, as similarly discussed further below with regard to FIGS.23A-24B, the embodiment shown in FIGS. 8A-8D can allow a secondaryoperation to be performed, such as to deposit additional material intothe downstream vasculature 559, by dissolving the clotted material onthe mesh portion 550 b. The mesh portion 550 b can be cleared such thatadditional material can be passed therethrough during the secondoperation. For example, after the implant has been placed and hasoccluded the vessel, the mesh portion 550 b can be cleared and flowthrough the implant can be restored by injecting a material, fluid, orsaline through the mesh portion 550 b. A catheter can be advanced untila distal end of the catheter is positioned adjacent to the mesh portion550 b. Thereafter, a material, fluid, or saline can be ejected from thedistal end of the catheter against the mesh portion 550 b. This ejectioncan serve to clear the thrombosed material mesh portion 550 b.

Accordingly, in some embodiments, the clinician can clear or unblock themesh portion 550 b to deposit further material in the target region in asecond procedure without puncturing, piercing, or otherwise damaging theimplant 520 b. After clearing the mesh portion 550 b, the clinician caninject additional material to the target region.

Additionally, in some embodiments, the clinician may elect to place asecond implant at the site of the first implant (see e.g., FIGS.24A-24B) without puncturing, piercing, or otherwise damaging the implant520 b.

Referring now to FIGS. 8B-8C, the cover member 544 b of the implant 520b can be initially expanded by introducing fluid or material 571 throughthe catheter lumen 570 into an interior chamber 573 formed between alayer of the cover member 544 b positioned against the catheter 510 anda layer of the cover member 544 b surrounding the support component 540.Accordingly, the cover component 544 b can be inflated by flushing thecover component 544 b prior to releasing or permitting expansion of thesupport component 540. The substantially closed end formed by the meshportion 550 b can allow an increase in fluid pressure within theinterior chamber 573 sufficient to inflate the cover component 544 buntil the cover component 544 b comes in contact with a vessel wall 561.

According to some embodiments, the mesh portion 550 b can be configuredto block or restrict flow therethrough when the fluid pressure is lessthan 240 mm Hg or 5 pounds per square inch (“psi”). However, for fluidpressures above 5 psi, the mesh portion 550 b can expand or deflect suchthat the plurality of pores, cells, apertures, perforations, incisions,windows, or other cuts opens to permit flow through the mesh portion 550b.

For example, in some embodiments, a fluid or material 571 can beinjected through the catheter lumen 570 and into the interior chamber573 such that the fluid or material 571 in the interior chamber 573 isat a pressure greater than 5 psi, such as between about 10 psi and about200 psi, between about 40 psi and about 180 psi, or between about 70 psiand about 140 psi. The delivery pressure can be varied by using certaindelivery mechanisms. For example, using a 5 mL syringe, the fluid ormaterial can be delivered at between about 80 psi and about 100 psi.Further, using a 3 mL syringe, the fluid or material can be delivered atbetween about 120 psi and about 140 psi. Furthermore, using a 1 mLsyringe, the fluid or material can be delivered at about 200 psi.

At such high fluid delivery pressures, the mesh portion 550 b can permitpassage of the material 571 (shown in FIGS. 8B-8D as an embolicmaterial) to the downstream portion 559 of the vessel when injectedthrough the catheter lumen 570. However, in some embodiments, after theimplant 520 b is released into the vessel 561 (see e.g., FIG. 8D), evenunder severely elevated systolic pressure (e.g., above 240 mm Hg orabout 4.6 psi), the mesh portion 550 b can be configured to block orrestrict flow through the mesh portion 550 b. Further, in someembodiments, a glue or embolic material and/or therapeutic compositioncan be injected and can tend to occlude the pores, cells, apertures,perforations, incisions, windows, or other cuts of the mesh portion 550b, thus sealing the mesh portion 550 b. The “seal” of the mesh portion550 b can be reversible, as discussed above.

In some embodiments, the mesh portion 550 b can also be configured suchthat the pores, cells, apertures, perforations, incisions, windows, orother cuts of the mesh portion 550 b define an open configuration and aclosed configuration. The open configuration can be achieved when thecover member 544 b is in a generally unexpanded configuration, asillustrated in FIG. 8A. When in the unexpanded configuration, material571 can be passed through the mesh portion 550 b. However, when asufficient amount of material 571 has been deposited into the downstreamvasculature 559 through the mesh portion 550 b, the support component540 can be expanded, thus causing expansion of the mesh portion 550 band, in some embodiments, shrinking of the pores, cells, apertures,perforations, incisions, windows, or other cuts of the mesh portion 550b. Thereafter, when a glue or embolic material is used, the glue orembolic material and/or therapeutic composition can act to further closeor seal the pores, cells, apertures, perforations, incisions, windows,or other cuts of the mesh portion 550 b. The “seal” of the mesh portion550 b can be reversible, as discussed above.

FIG. 9A-10B illustrate embodiments of an implant 520 c being deliveredusing different catheters, which can provide unique benefits andadvantages. FIGS. 9A and 10A, illustrate an implant 520 c having a valvecomponent 542 c that comprises a flap structure 550 c. The flapstructure 550 c can comprise a flat plate that is attached to a distalend 560 of the cover member 544 c or to a distal end of the supportcomponent 540. The flap structure 550 c can be resiliently biased towarda closed position (as shown in FIGS. 9A and 10A) in which the flapstructure 550 c covers an aperture 562 of the implant 520 c.

However, upon expansion of the implant 520 c (illustrated as expansionof a distal portion 548 c of the implant 520 c in FIGS. 9B and 10B),proximal foreshortening of the implant 520 c can cause a distal tip 564of the catheter 510, 510′ to be advanced distally relative to theimplant distal portion 548 c, thus contacting against the flap structure550 c. When the distal tip 564 presses against the flap structure 550 c,the flap structure 550 c will tend to deflect from the closed position,thus opening the lumen of the implant 520 c such that it is in fluidcommunication with the lumen of the vessel into which the implant 520 cis being deployed. The distal tip 564, 564′ of the catheter 510, 510′can then move distally beyond the distal portion 548 c of the implant520 c, and as shown, have a clear outflow pathway for material injectedthrough the catheter 510, 510′.

Further, the catheter 510, 510′ can comprise a material delivery lumen570 through which material can be passed toward the target region. Thecatheter 510 can also comprise a distal port 572, 572′ in communicationwith the lumen 570. As noted above, when the catheter distal tip 564,564′ moves distally beyond the distal portion 548 c of the implant 520c, the port 572, 572′ will provide a clear outflow pathway for materialinjected through the lumen 570. The port 572, 572′ can therefore bemoved into a position in which it is in unobstructed, fluidcommunication with the target region, as illustrated in FIGS. 9B and10B. Accordingly, material can then be delivered through the lumen 570and out through the port 572, 572′ into the target region. The lumen 570can also be used to flush the implant or pass other fluids through theimplant or toward a downstream section of the blood vessel.

In some embodiments, the catheter 510 can comprise a fiber deliverylumen opposite material delivery lumen 570 through which an opticalfiber can be disposed wherein the optical fiber can deliver a laser suchas but not limited to erbium:yttrium-aluminium-garnet (Er:YAG) laserwith a wavelength of 2.9 μm, high frequency (HF) laser with a wavelengthof 2.8 μm, carbon monoxide (CO) laser with a wavelength of 5.3 μm, orcarbon dioxide (CO₂) laser with a wavelength of 10.6 μm. In otherembodiments, the optical fiber delivers infrared light having awavelength of about 850 nm to 1550 nm or of about 850 nm, 1300 nm, or1550 nm. In still other embodiments, the optical fiber deliversnear-infrared light having a wave length of about 650 nm to 950 nm.Accordingly, in some embodiments, the lumen 570 encases an opticalfiber. In other embodiments, the catheter is co-molded or over-moldedonto the optical fiber. Using methods known to the ordinarily skillartisan, the laser is applied to provide a therapeutically effectiveamount of light or energy, time of exposure, and depth to the regionexposed to the therapeutic material. The optical fiber can traverse thelength of the catheter and can be controlled using the deployment handleand/or actuation mechanism described herein.

Accordingly, a distal end portion of the optical fiber can be positionednear the region containing the cancerous tissue, although the opticalfiber can be manipulated independently of the support structure. Thesize of the optical fiber is referred to herein by the outer diameter ofits core, cladding and coating and will be a size which can fit withinthe delivery catheter. In some embodiments, the fiber has a corediameter of 50 μm, a cladding diameter of 125 μm, and a coating diameterof 250 μm. In other embodiments, the optical fiber has a coatingdiameter less than 250 μm. It is understood that if fibers need to bejoined or connected together, the coating is removed.

FIGS. 9A-9B illustrate that the distal tip 564 of the catheter 510 cancomprise a generally flat face that is oriented substantially orthogonalrelative to the longitudinal axis of the catheter 510. In suchembodiments, the distal tip 564 can be moved relative to the distalportion 548 c of the implant 520 c until the flap structure 550 c ismoved away from the closed position shown in FIG. 9A toward the openposition shown in FIG. 9B, thereby allowing the port 572 to have a clearoutflow pathway for material to be ejected from the lumen 570.

FIGS. 10A-10B illustrate an embodiment of the distal tip 564 in whichthe port 572′ is facing generally downward or radially outward relativeto the longitudinal axis of the catheter 510′. Such embodiments canprovide an advantageous beveled or angled configuration, which may needto move the flap structure 550 c only a short length or make a singlepoint of contact in order to achieve a clear outflow pathway for thematerial to be ejected from the lumen 570. According to someembodiments, the bevel of the catheter 510′ can be modified such thatthe catheter 510′ defines a generally conical tip or the bevel can beremoved entirely such that the distal tip 564 is generally flat, asillustrated in FIGS. 7A-7B, 9A-9B, and 11A-12B.

After the desired saturation or amount of embolic material beenreleased, the implant 520 c can be entirely removed from the vessel orimplanted at the target region. For example, a proximal portion 549 c ofthe implant 520 c can be released and allowed to expand into appositionwith the vessel wall. Thus, in accordance with some procedures, materialcan be released into the target region and flow through the vessel canbe occluded using the implant 520 c, thereby inducing infarction of thetarget region.

FIGS. 11A-12B illustrate additional embodiments of an implant 520 chaving a valve component 542 d and movement of the catheter distal end564 distally beyond the implant distal end. For example, FIGS. 11A-11Billustrate a dome-shaped valve component 542 d. The dome-shaped valvecomponent 542 d can comprise a pair of opposing, flexible half-domestructures 580 that can be biased toward each other such that a slit orgap between the structures 580 is in a substantially closed position.

Similar to the discussion above regarding the embodiment in FIG. 9A-9B,the distal end 564 of the catheter 510 can be urged or moved through theaperture 562 of the implant 520 d, thus contacting the structures 580and causing separation thereof, such that the gap or slit between thestructures 580 is opened and the lumen 570 of the catheter 510 is placedin fluid communication with the target region, as shown in FIG. 11B.

Additionally, FIGS. 12A-12B illustrate an embodiment of an implant 520 ehaving a valve component 542 e, in the form of an iris diaphragm-typevalve structure. The valve component 542 e can comprise a plurality offlexible leaflets or structures 590 that can be biased toward each othersuch that an aperture 592 between the structures 590 is in asubstantially closed position.

Similar to the discussion above regarding the embodiment in FIG. 9A-11B,the distal end 564 of the catheter 510 can be urged or moved through theaperture 562 of the implant 520 d, thus contacting the structures 590and causing separation thereof, such that the aperture 592 between thestructures 590 is opened and the lumen 570 of the catheter 510 is placedin fluid communication with the target region, as shown in FIG. 12B.

In addition to the embodiments discussed above, which can be carried ona distal engagement section of the catheter, other embodiments can beprovided in which the implant is delivered by distally advancing theimplant through a lumen of the catheter. Thus, instead of engaging theimplant externally to the catheter, the implant can be advancedinternally to the catheter, such as by pushing or pulling the implantthrough the lumen. In some embodiments, support and valve components ofthe implant can be collapsed into an elongate position and released intoan expanded position within the vessel. Features and aspects of theimplants, including the support component and the valve component, arealso disclosed in co-pending U.S. Application No. 61/904,376, filed Nov.14, 2013, titled Implantable Luminal Devices and Methods (086538-0041),the entirety of which is incorporated herein by reference. Further, anyof the valve components disclosed herein (see e.g., FIGS. 7A-16B) can beused with a helical support component that can be coupled to a catheter(as shown in FIGS. 3-12B) or a deflectable support component that can beat advanced within a catheter (as shown in FIGS. 13-16B), including anycombinations or modifications thereof.

For example, referring to FIGS. 13-14A, the implant can be deliveredthrough a lumen of the catheter. As shown, a catheter 610 can beprovided that comprises a lumen 612 configured to receive the implant620 therein. The implant 620 can comprise a support component 622 and acover component 624. FIG. 13 illustrates the implant 620 in a collapsed,elongated configuration, which enables the implant 620 to be movedwithin the catheter lumen 612.

The support component 622 and the cover component 624 can be attached toeach other or be separated and freely movable relative to each other.Whether attached or separated, the support and cover components 622, 624can be configured to be advanced through the catheter lumen 612together, as a single unit. For example, FIG. 13 also illustrates that,according to some embodiments, the support component 620 can be at leastpartially enclosed, enveloped, or covered by the cover component 624such that the support component 622 and the cover component 624 can beattached to each other and delivered together (and as shown in FIG. 14A,released into the vessel together).

However, according to some embodiments, the support and cover component622, 624 can be separated from each other and moved through the catheterlumen 612 independently of each other. For example, the implant 620 canalso be configured such that the support component 622 is deployed intothe cover component 624 after the cover component 624 has beenpositioned within the vessel.

Once the implant 620 reaches the target area, FIG. 14A illustrates thatthe implant 620 can be expanded from the collapsed configuration to anexpanded configuration. In the expanded configuration, the supportcomponent 622 of the implant 620 can increase in its diameter, expandingwithin the cover component 624. In either embodiment, whether thesupport component 622 and the cover component 624 are attached to eachother or separated and freely movable relative to each other, when thesupport component 622 expands, the support component 622 can press thecover component 624 against a side wall of the lumen and thereby fix thecover component 624 (and the implant 620) within the lumen.

The cover component 624 can comprise a valve component 626 and a sheathportion 628. The valve component 626 and the sheath portion 628 can forma substantially continuous sleeve or layer (e.g., having a seal betweenthe valve component 626 and the sheath portion 628 such that fluidpasses only through an aperture or opening of the valve component 626)into which the support component 622 can expand. The aperture or openingcan have a size between about 100 microns and about 3,000 microns, about500 microns and about 2,800 microns, or about 1,000 microns and about2,500 microns. The sheath portion 628 can be porous, nonporous, and/orcomprise one or more portions that are nonporous, such as impermeablegraft or other such sections.

Additionally, as illustrated above and in FIG. 13, as with variousembodiments discussed herein, the support component 622 having dual wireloop features can be held in a generally linear or straightconfiguration within a lumen 612 of a catheter 610. The loops 630 (shownin the expanded configuration illustrated in FIG. 14A) of the supportcomponent 622 can be pulled or longitudinally stretched to createtension between open loops 630 to allow the support component 622, whendeployed, to spring back to or return to an expanded shape consisting ofvarious expanded loops 630, as illustrated in FIG. 14A, as the supportcomponent 622 exits from a distal end 632 of the catheter 610.

The support component 622 of the implant 620 can be configured asillustrated in FIGS. 13-16B, and as shown and described in co-pendingU.S. Application No. 61/835,406, filed Jun. 14, 2013, titled ImplantableLuminal Devices and Methods (086538-0032), the entirety of which isincorporated herein by reference. Further, various other configurationscan be used, such as those disclosed in co-pending U.S. Application No.61/904,376, filed Nov. 14, 2013, titled Implantable Luminal Devices andMethods (086538-0041). Accordingly, a support component can compriseseparate wires that are preset into shapes that are generally mirrorimages of each other along a longitudinal center plane (extendingthrough the central axis) of the support component, as illustrated inFIGS. 13-14A. The wires extend from a first end to a second and of thesupport component and can be joined or connected together, eithermechanically or chemically, to form the support component.

FIGS. 12-16B illustrate embodiments of implants having a supportcomponent and a valve component, which can be delivered by advancing theimplant within the lumen of the catheter as opposed to being supported,engaged, or restrained along an exterior surface of the catheter.

FIGS. 14B-14C illustrate an implant 650 having a support component 652,a valve component 654 a, and a cover component 656. The supportcomponent 652 can be configured as illustrated and described above withrespect to the support component 622 shown in FIGS. 13-14B. The valvecomponent 654 a can comprise a movable component 660 that can beattached to a first end 662 of the support component 652. The movablecomponent 660 can be movable between an open position 670 and a closedposition 672. In the open position 670, the movable component 660 can bespaced apart from the first end 662 of the support component 652 suchthat fluid can flow between the first end 662 and an outer perimeter 674of the movable component 660. In the closed position 672, the valvecomponent 654 a can serve to prevent retrograde (and in someembodiments, anterograde flow) through the valve component 654 a. Suchembodiments can be useful to prevent displacement of embolic and/ortherapeutic material outside of the target region, such as into upstreamportions of the vessel, or undesired dilution of the embolic material inthe target region.

In accordance with some embodiments, the movable component 660 can bemoved relative to the first end 662 in response to pressure or alongitudinal force exerted against the movable component 660. Forexample, the movable component 660 can move away from the supportcomponent 652 (e.g., from the closed position 672 toward the openposition 674 shown in FIG. 14B). The movable component 660 can be biasedtoward the closed position 672 such that the movable component 660returns to the closed position 672 after being urged toward the openposition 674. In the closed position 672, the movable component 660 canprevent retrograde flow through the valve component 654 a.

For example, the movable component 660 may move toward and away from thenonmovable component 682. With blood flow entering the opening 684 inthe nonmovable component 682, the smaller, movable component 660 canseparate from the nonmovable component 682, thus creating a space forblood to pass. At a pressure less than a normal systolic pressure (e.g.,less than about 120 mm Hg, less than about 110 mm Hg, less than about100 mm Hg, less than about 90 mm Hg, or less than about 80 mm Hg), themovable component 660 can return or fall back against at least thenonmovable component 682, thus at least partially closing the opening684 or sealing against retrograde or backflow through the vessel.

The movable component 660 can be coupled relative to the first end 662.For example, the movable component 660 can be attached using at leastone fastener 680. The fastener 680 can be elastic, resilient, flexible,or inelastic. The fastener 680 can comprise at least one hinge-typefastener, a strap-type fastener, and/or material having one or moreapertures extending therethrough such that fluid or material can passout of the first end 662 of the implant 650 past the movable component660 when the movable component 660 is in the open position 670. Thus, asillustrated in FIG. 14B, the movable component 660 can be attached usinga plurality of fasteners 680 (shown as flexible strap-type fasteners)that permit anterograde flow out of the implant 650 past the movablecomponent 660. The movable and/or nonmovable components 660, 682 can beconnected by bands, strips, or ribbons so that the movable component 660may move to and from the nonmovable component 682 freely.

According to some embodiments, the valve component 654 a can alsocomprise a nonmovable component 682. The nonmovable component 682 can beattached to the support component 652. The nonmovable component 682 cancomprise a material formed separately from and later attached to thesupport component 652. The nonmovable component 682 can comprise aplate, three-dimensional structure, a wire, or other feature that isattached to, dried onto, or otherwise coupled to the support component652. For example, the nonmovable component 682 can be coupled to thedistal end 662 of the support component 652 such that the nonmovablecomponent 682 does not move longitudinally relative to the supportcomponent 652. In some embodiments, the nonmovable component 682 can befixed relative to the support component 652.

The nonmovable component 682 can comprise at least one opening 684through which fluid or material passing through the lumen of the implant650 can flow and exit the lumen of the implant 650. The opening 684 cancomprise one or more apertures that are formed in the nonmovablecomponent 682. The movable component 660 can have a size greater thanthe size of the opening 684 such that when positioned over the opening684, the movable component 660 can block flow through the opening 684.

In some embodiments, the nonmovable component 682 and the movablecomponent 660 can be configured to nest, mate, or be positioned flushagainst each other when the valve component 654 a is in the closedposition. In such embodiments, the nested, mated, or flush positioningof the nonmovable and movable components 682, 660 can allow the valvecomponent 654 a to at least partially obstruct or fully block flowthrough the valve component 654 a when in the closed position.

For example, the nonmovable component 682 and the movable component 660can each have shapes that correspond to each other and permit the valvecomponent to at least partially obstruct or fully block flowtherethrough. In some embodiments, the nonmovable component 682 can havea substantially flat or planar shape and the movable component 660 canalso have a substantially flat or planar shape. Such an embodiment asillustrated in FIGS. 14B-14C, where in the closed position of FIG. 14C,backflow against the valve component 654 a would cause the movablecomponent 662 be positioned flush against the nonmovable component 682,thus preventing flow through the opening 684.

Further, in some embodiments, the nonmovable component 682 can have acurved or arcuate shape and the movable component 660 can also have acurved or arcuate shape. As illustrated in FIGS. 14A-14C, the movablecomponent 660 can comprise a substantially conical shape. In someembodiments, for example, the nonmovable component 682 can also comprisea substantially conical shape such that the movable and nonmovablecomponents 660, 682 can self-center when in contact with each other orhave a self-centering function. Furthermore, in some embodiments, theshape of the nonmovable and movable components 682, 660 can comprisemating components such that the nonmovable and movable components 682,660 assume a substantially fixed rotational orientation relative to eachother when the valve component 654 a is in the closed position (e.g.,when the nonmovable and movable components 682, 660 are nested or matedagainst each other).

In some embodiments, the movable and/or nonmovable components 660, 682can be formed from a film layer, such as a fabric or other polymer(e.g., ePTFE) film that is attached to one or more of the loops of thesupport component 652. As shown, the nonmovable component 682 cancomprise an annular or doughnut-shaped component, and the movablecomponent 660 can comprise a solid round panel that is oversizedrelative to the opening 684 in the nonmovable component 682.

Referring now to FIGS. 15A-15B, other embodiments of a valve componentis shown. In this embodiment, a valve component 654 b can be used withthe support component 652 and the cover component 656 of the implant650. As discussed above similarly with regard to the valve component 654a, the valve component 654 b can function to allow anterograde flowwhile substantially preventing retrograde flow through the implant 650.

In the embodiment illustrated in FIGS. 15A-15B, the valve component 654b can be configured as a plurality of movable panels 690 that can fold,bend, deflect, or otherwise move from a closed position 692 (FIG. 15A)to an open position 694 (FIG. 15B). For example, the valve component 654b can comprise a single layer or sheet of material having at least onecut to form at least two moving edges that can be displaced relative toeach other in order to form an aperture or opening 696 between theedges. In FIG. 15B, the edges are formed by four intersecting cuts(e.g., intersecting generally perpendicularly), thus forming sixteenmovable edges and eight movable panels 690. However, the valve component654 b can be configured to have two, three, four, five, six, seven, ormore panels.

The valve component 654 b can comprise an elastic, flexible, ordeflectable material that can be biased to maintain the closed position692 unless a threshold level of pressure is met, such as pressureexceeding a normal systolic pressure (e.g., about 120 mm Hg). Further,the valve component 654 b can move toward the closed position 692 whenthe pressure is below a normal systolic pressure (e.g., less than about120 mm Hg, less than about 110 mm Hg, less than about 100 mm Hg, lessthan about 90 mm Hg, or less than about 80 mm Hg).

Further, as shown in FIGS. 16A-16B, a valve component 654 c can also beprovided in which the single layer or sheet of material has athree-dimensional shape, such as a dome, cone, pyramid, wedge, or othershapes. In FIGS. 16A-16B, the material of the valve component 654 c hasa single cut forming opposing edges 700 that can move relative to eachother in order to open or close an aperture 702 of the valve component654 c in open or closed positions 710, 712. Multiple cuts can also bemade in three-dimensionally shaped valve components. Alternatively, thevalve component 654 c can be formed from separate hemisphericalcomponents that are aligned and attached to the support component 652 inorder to permit relative movement between the hemispherical componentsto open or close the aperture 702 in response to pressure fluctuations.Such components can be deflectable or rigid.

In some embodiments, the edges 700 of the aperture 702 can comprise aframe element. Both of the edges 700 can have a frame element extendingtherealong. The frame element can function to maintain an arcuate shapeof the edges 700 such that the edges 700 can reliably meet and avoidgapping or spaces therebetween when the edges 700 meet in the closedposition (as shown in FIG. 16A). In some embodiments, the frameelement(s) can be a section of the support component 652 that extendsfrom the loop of the first end 662 of the support component 652. Thus,in accordance with some embodiments, the frame element(s) can aid,support, or provide the biasing force to urge the opposing edges 700toward the closed position 710.

As noted above with respect to the valve components 654 a, 654 b, thevalve component 654 c can also comprise an elastic, flexible, ordeflectable material that can be biased to maintain the closed position710 unless a threshold level of pressure is met, such as pressureexceeding a normal systolic pressure (e.g., about 120 mm Hg). Further,the valve component 654 c can move toward the closed position 710 whenthe pressure is below a normal systolic pressure (e.g., less than about120 mm Hg, less than about 110 mm Hg, less than about 100 mm Hg, lessthan about 90 mm Hg, or less than about 80 mm Hg).

Methods of Material Delivery

According to some embodiments disclosed herein, procedures, techniques,and implants are provided by which an implant can be deployed into abody lumen in order to deliver a material (e.g., embolic material,therapeutic material, contrast agents, or drugs) to a target bodyregion.

In some embodiments, the procedure can be performed such that one ormore implants is fully expanded into contact with the lumen and releasedthereat in order to at least partially occlude flow through the lumen.Thereafter, the material can be injected through an aperture or valve ofthe implant into the lumen at a location downstream of the implant.

In addition, the implant can be left in place to at least partiallyocclude the lumen after the material has been delivered. In someinstances, the implant can fully or at least substantially occlude thelumen immediately after its release into the lumen. In order to do so,the aperture or valve of the implant is closed.

The valve component of the implant can be configured to become at leastpartially closed once the catheter carrying the implant is withdrawn andthe implant is fully released into the lumen. For example, the valvecomponent can be at least partially closed or sealed to at least a frameof the implant, thereby at least partially closing or sealing theimplant distal portion. The valve component can be closed or sealedusing embolic material, adhesives, or other such materials.

In some embodiments, as discussed above, a portion of the catheter canbe configured to move beyond or through the distal portion of theimplant or have a close fit with the implant in order to preciselydeliver a material into the lumen downstream of the implant and avoiddispersion or diffusion of the material upstream of the implant.

For example, the implant proximal portion can be maintained engaged withthe catheter while the implant distal portion is allowed to expand intocontact with the vessel wall (see e.g., FIGS. 17A-17D, 19A-19C, and20A-20D). In some embodiments, the expansion of the implant distalportion can cause the implant to foreshorten and thus cause the distalportion of the catheter to move beyond or through the distal portion ofthe implant. Further, in some embodiments, the catheter may not movebeyond or through the distal portion of the implant, but the implantdistal portion can be open thereby permitting free flow of material fromthe catheter distal tip (see e.g., the implant illustrated in FIGS.7A-7D). Thereafter, material can be injected into the lumen, thusavoiding dispersion or diffusion of the material upstream of theimplant.

However, in some embodiments, the implant distal portion can bemaintained engaged with the catheter while the implant proximal portionis allowed to expand into contact with the vessel wall (see e.g., FIGS.18A-18D), whereafter material can be injected into the lumen, thusavoiding dispersion or diffusion of the material upstream of theimplant.

Reflux of material against the implant (e.g., embolic or adhesivematerial) can cause at least a portion of the implant to become closed(see e.g., FIGS. 7C-7D). The implant can use a polytetrafluoroethylene(“PTFE”) or expanded polytetrafluoroethylene (“ePTFE”) cover member thathas a plurality of ribbons extending distally and around an aperture inthe distal portion of the implant. Although the ribbons will not tend toblock anterograde flow through the aperture, reflux or retrograde flowof the embolic material can cause the ribbons to contact each other,adhere to one another, and become joined together as a mass that clogsand blocks the distal aperture of the implant, thereby closing orsealing the implant, as shown in FIG. 7D, for example. Such an implantconfiguration is discussed in co-pending U.S. patent application Ser.No. 14/044,794, filed Oct. 2, 2013, the entirety of which isincorporated herein by reference.

Further, the valve component can be closed mechanically, such as bybeing biased toward a closed position. Mechanical biasing can cause thevalve component to be released and move toward its closed position oncethe implant is released and disengaged from by the catheter.

Referring initially to FIGS. 17A-20D, a clinician can use an embodimentof the implant disclosed herein (illustrated as the implant shown inFIGS. 7A-7D) to deposit embolic particles into a target body region. Asshown in FIGS. 17A, 18A, and 20A, a guide catheter 760 can be advancedto a target region of a lumen 752 of a blood vessel 750. The vessel 750can be an artery. Optionally, the guide catheter 760 can be advanced tothe target region over a guidewire. Guidewires used in accordance withany of the embodiments disclosed herein can have a size of between about0.005 inches and about 0.030 inches, between about 0.008 inches andabout 0.024 inches, or between about 0.010 inches and about 0.018inches, such as 0.010 inches, 0.014 inches, or 0.018 inches.

An implant carrier assembly 762 can be advanced to the target region. Insome embodiments, the implant carrier assembly 762 can be advancedthrough the catheter 760 toward a distal portion of the catheter 760, asshown in FIGS. 17A, 18A, and 20A. However, in some embodiments, thecatheter 760 can also be omitted and the implant carrier assembly 762can be advanced to the target region over a guidewire, such as thatmentioned above.

For example, FIGS. 19A-19C illustrate that methods or proceduresdisclosed herein can also omit the guide catheter 760. As shown, theimplant carrier assembly 762 can be advanced along a guidewire 767 untilreaching the target region. A supporting catheter 764 of the carrierassembly 762 can comprise a lumen that is configured to receive theguidewire 767 to facilitate distal advancement without a guide catheteror other member. Thus, in such embodiments, the supporting catheter 764and an implant 766 carried thereon can reach much smaller vessels orarteries than in embodiments that require a guide catheter 760.

Thus, in some embodiments, including that illustrated in FIGS. 19A-19C,the implant 766 can be placed in vessels or arteries ranging in sizefrom about 1.2 mm to about 6.5 mm, from about 1.4 mm to about 6.0 mm,and about 1.7 mm to about 3.0 mm.

The implant 766 and the supporting catheter 764 can have a passingprofile or outer diameter of between about 3 Fr and about 8 Fr, or thatcan be compatible with a guide catheter having a size of between about 3Fr and about 12 Fr. Further, as similarly noted above, the guidewire 767can have a size of between about 0.005 inches and about 0.030 inches,between about 0.008 inches and about 0.024 inches, or between about0.010 inches and about 0.018 inches, such as 0.010 inches, 0.014 inches,or 0.018 inches.

When used, as shown in FIGS. 17A, 18A, and 20A, the guide catheter 760can be proximally withdrawn from the vessel 750, as shown in FIGS. 17B,18B, and 20B. Thus, the implant carrier assembly 762 can be positionedat the target region whether by use of a catheter 760 or not, as shownin FIGS. 17B, 18B, 19A, and 20B.

Next, referring to FIGS. 17C, 18C, 19B, and 20C, using the deploymenthandle or actuation mechanism, the clinician can expand a first orsecond portion (or both) of the implant 766 in order to at leastpartially or fully occlude flow past the implant 766 into a downstreamsection 770 of the lumen 752. The deployment handle can be configuredsuch as those disclosed herein and/or in co-pending U.S. patentapplication Ser. No. 14/044,794, filed Oct. 2, 2013, the entirety ofwhich is incorporated herein by reference. This blockage of downstreamflow through the vessel can make possible a highly targeted andconcentrated delivery of a therapeutic material to a target region,avoiding dilution of the material in the downstream section 770 orreflux of the material 768 into an upstream region 772 of the vessel750.

For example, in some embodiments, such as that illustrated in FIGS. 17C,18B, and 19C, the clinician can expand a distal portion 780 of theimplant 766 while maintaining a proximal portion 782 of the implant 766in a closed state. Thus, the distal portion 780 can expand intoapposition with a wall of the vessel 750, thereby occluding,substantially or fully, flow through the vessel to the downstreamsection 770 of the lumen 752. Accordingly, the downstream section 770 ofthe lumen 752 can be isolated from the upstream section 772 of the lumen752. This occlusion or isolation can enable the clinician to provide amore targeted delivery of material 768 to a target region and avoiddilution of the material 768 in the downstream section 770 or reflux ofthe material 768 into an upstream region 772 of the vessel 750.

Further, in some embodiments, such as that illustrated in FIG. 18C, theclinician can expand the proximal portion 782 of the implant 766 whilemaintaining the distal portion 780 of the implant 766 in a closed state.Thus, the proximal portion 782 can expand into apposition with a wall ofthe vessel 750, thereby occluding, substantially or fully, flow throughthe vessel to the downstream section 770 of the lumen 752. A flushingport, such as that illustrated in the embodiments of FIGS. 1 and 2, canbe used to inject fluid into the proximal portion 782 in order tofacilitate expansion thereof. Once expanded, as with the embodimentillustrated in FIG. 17C, the downstream section 770 of the lumen 752 canbe isolated from the upstream section 772 of the lumen 752. Thisocclusion or isolation can enable the clinician to provide a moretargeted delivery of material 768 to a target region and avoid dilutionof the material 768 in the downstream section 770 or reflux of thematerial 768 into an upstream region 772 of the vessel 750.

After flow has been at least partially occluded, FIGS. 17C, 18C, 19B,and 20C illustrate that the clinician can release a desired material 768into the downstream section 770 of the lumen 752. The desired material768 can comprise an embolic material, such as NBCA glue, liquid embolicagents, a radiopaque material, a radioactive material, drugs or othertherapeutic materials. As described in more detail herein, the materialis a therapeutic material which can comprise one or more therapeuticagents as described herein which are effective for treating canceroustissues or tumors. Such therapeutic agents include but are not limitedto metal nanoparticles, radiosensitizers, chemotherapeutic agents,radioembolics, and photothermal agents. The release of such material 768into the downstream section 770 of the lumen 752 can be performed untila desired amount or concentration of such material 768 is achieved inthe downstream section 770.

In some embodiments, after desired material has been delivered and ifthe implant is to remain in place within the lumen, material immediatelyadjacent to the valve component of the implant can function to at leastpartially close or seal the valve component. For example, in embodimentssuch as those that use the implant illustrated above in FIGS. 7A-7D, anadhesive material can be released at the end of the process in order toallow the implant to self-seal. Further, in embodiments in which theimplant is biased toward a closed position (see e.g., the valvecomponent in FIGS. 9A-12B), the material (especially glues or otheradhesive-type materials) can facilitate the creation of an at leastpartially closed or sealed valve that no longer permit flow through andout of the implant to the downstream section of the vessel. Further, thematerial can tend to facilitate thrombosis or coagulation of blood tofurther occlude the lumen (see e.g., FIGS. 8A-8B).

In some embodiments, the remaining portion of the implant 766 isexpanded or released and the catheter 764 can be removed from the vessel750, as shown in FIGS. 17D, 18D, and 19C. However, in some embodiments,the implant 766 and the catheter 764 can be removed from the vessel 750.For example, FIGS. 20C-20D illustrate that the guide catheter 760 can bemaintained adjacent to the implant 766 such that after material has beendeployed from the assembly 762, the assembly 762 can be proximallywithdrawn into the guide catheter 760. In some embodiments, the guidecatheter 760 can be distally advanced over the assembly 762 such thatthe implant 766 is not moved relative to the blood vessel 750.

According to some embodiments, implants can be deployed in lumens havingdimensions of between about 2 mm and about 20 mm. The target deliveryprofile can be about 6 Fr or smaller. For example, the implant assemblycan be compatible with a guide catheter having a size of between about 3Fr and about 12 Fr.

According to some embodiments, implants disclosed herein can have afibrous membrane feature can be used in various clinical applications,as discussed above. According to some embodiments, implants disclosedherein having a fibrous membrane feature can have an expanded diameterof between about 3 mm and about 22 mm.

In addition, the methods and procedures discussed above with respect toFIGS. 17A-20D can be implemented in accordance with further aspect shownin FIGS. 21-24B. For procedures that deliver an embolic agent or othertherapeutic material comprising, for example, radioactive particles,metal nanoparticles, or thermoactive agents for additional radiologicalor thermal treatment of a tumor, the procedure must precisely deliverthe material the target region. Such delivery must be well-controlleddelivery and calibrated in order to protect a patient from theunnecessary additional risks that may occur should the material beingimproperly distributed within other areas of the downstream vasculature.

For example, FIG. 21 illustrates an embodiment of a procedure in which afirst implant 800 is deployed into a vessel 802 adjacent to a targetstructure, vasculature, or lesion 804. The target structure 804 can befed by a series of arteries 806. After placing the first implant 800 ina location downstream of the arteries 806 to prevent flow of a deliveredmaterial (e.g., embolic material) to downstream vasculature, an implantassembly 810 can be advanced to a location within the vessel 802 that isproximal to the target arteries 806 and the first implant 800. Theimplant assembly 810 and the first implant 800 can be spaced apart inclose proximity to each other to allow flow to only those targetarteries 806 and to shield flow to other unintended areas. For example,the implant assembly 810 and the first implant 800 can be spaced apartin a range of from about 0.1 inches to about 5 inches, about 0.5 inchesto about 3 inches, about 0.8 inches to about 2 inches, about 1 inches toabout 1.5 inches, or about 1.2 inches to about 1.4 inches. Variousranges of spacing between the implant 800 and the assembly 810 can beachieved to precisely target a region of the vessel 802 and/or selectarteries 806.

In the illustrated embodiment of FIG. 21, a distal portion of a secondimplant 820 is expanded into apposition with the walls of the vessel 802in order to at least partially block anterograde flow to the arteries806. A material 822 can then be released into the space between thefirst and second implants 800, 820. The material can thus beconcentrated toward the arteries 806, thereby enhancing the efficacy ofthe delivery. Thereafter, additional steps or procedures can beperformed, such as imaging, in order to further treat the vessel 802 ortarget structure 804. In some embodiments, after release of material 822wherein material is a therapeutic material, an optical fiber asdescribed herein can be activated to emit light such as infrared or nearinfrared light to activate the particles such as gold/iron oxidenanoparticles, wherein activation results in an increase in temperatureof the environment surrounding the nanoparticles. In some embodiments,the distal end of the optical fiber is advance to approximately thedistal end of the implant assembly 810 or to the distal, open end of thesecond implant 820 prior to light emission. In still other embodiments,the optical fiber is coupled to a catheter of implant assembly 810 asdescribed herein, such as wherein a catheter is co-molded or over-moldedwith the optical fiber.

As noted above, the first and/or second implants 800, 820 can bereleased and left in the vessel 802 in order to provide occlusion of thevessel. However, according to some embodiments, one or both of the firstor second implants 800, 820 can be removed from the vessel 802 after thematerial has been delivered to the arteries 806 and target structure804. Thus, procedures can be provided that allow temporary occlusion ofa blood vessel in order to treat a target structure while thereafterbeing able to restore blood flow through the previously occluded artery.

FIG. 22 illustrates the delivery of a material 822 toward arteries 806and a target structure 804. In this embodiment, an implant assembly 810has been advanced to a location adjacent to the target structure 804.Thereafter, the implant 820 is expanded into apposition with the wallsof the blood vessel 802. The material 822 can then be released into thedownstream areas of the vessel 802 and arteries 806. Thus, the material822 can be advanced downstream toward the target structure 804.Thereafter, the implant 820 can be expanded and released, such thatblood flow to the target structure 804 is restricted or eliminated, thusinducing infarction of the target structure 804.

Such embodiments advantageously mitigate any upstream migration of thematerial 822 toward an upstream section 832 of the vessel, and can tendto enhance or increase the concentration of material delivered to thearteries 806 and target structure 804. In some embodiments, theprocedure can also mitigate any downstream migration of the material 822toward a downstream section 830 of the vessel. Further, such adual-implant system or procedure can also mitigate any upstreammigration of the material 822 toward an upstream section 832 of thevessel 802. Embodiments of this technique allow confident and preciseapplication of material in any of a variety of situations, such as thosementioned above.

As discussed herein and as illustrated with respect to FIGS. 17A-22,various treatment procedures can be performed for a target body region,such as tumor devascularization, reducing traumatic bleeding orhemorrhage, high-flow vascular malformations, vascular or airway volumereduction procedures, treatment of a target lesion, treatment andembolization of incompetent venous systems in low extremities (e.g.,legs and lower abdominal area), treatment varicose veins in the leg(e.g., great saphenous vein and spider veins in deeper system),attending to other indications such as AVM, pelvic varices, etc. Othertreatment procedures may include delivery of therapeutic materials asdescribed herein which are effective in treating a disorder such as acancer or other hyperplasia disorder. In some situations, a singletreatment may not be sufficient to fully devascularize, heal, orotherwise treat the target body region.

Therefore, according to some embodiments, after a first treatment orprocedure in which a first occlusive implant has been released into avessel or artery and remained thereat, at least partially occluding thevessel for a given period of time, a second procedure can be performedto remove and/or modify the first occlusive implant using the catheterand/or a second occlusive implant.

For example, depending on the therapeutic strategy, if a clinicianbelieves that the target body region may benefit from a second treatmentor procedure, a second procedure can be undertaken in which the firstocclusive implant can be removed and/or modified. The second procedurecan be performed after one, two, three, four, five or six months, orlonger, and depends on the health of the patient and need for such aprocedure.

The second procedure can be performed by removing the first implantand/or modifying the first implant, such as by restoring flow through avalve of the first implant. The first option for the second procedurecomprises removing the first implant from the vessel using a removaldevice. After removal, the first implant can be replaced by a new,second implant.

Another option for the second procedure comprises modifying the firstocclusive implant, such as by restoring flow through the first implant,physically altering the first implant 970 (see FIGS. 23A-23B), injectingadditional material toward the target region, and/or inserting a secondimplant 980 into the first implant 970 (see FIGS. 24A-24B) so as tochange the effect or degree of the occlusion or permit additionalmaterial to be deployed downstream of the first implant 970.

In some embodiments, the first implant 970 can be modified bypenetrating or punching a hole or aperture in the cover member orotherwise removing a portion of the first implant 970. The punching cancomprise disconnecting, opening, or otherwise tearing a valve componentfrom the first implant distal portion. The hole or aperture can be madein order to restore flow at least partially through the first implant970, thereby allowing revascularization of the target body region.

For example, FIG. 23A illustrates that when the first occlusive implant970 is left in the vessel 802, the clinician can advance a catheter,wire, or other adjustment member 972 to the target body region where thefirst implant 970 is deployed. When the adjustment member 972 ispositioned adjacent to the first implant 970, the adjustment member 972can be used to create a hole or aperture in the distal portion of thefirst implant 970 by advancing a distal tip of the adjustment member 972through the membrane or cover member of the first implant 970, asillustrated in FIG. 23B.

Thus, if determined appropriate, such revascularization can provide thefinal step to the procedure and no further occlusion may be necessary.However, as necessary, additional optional steps can be taken to occludeor otherwise treat the target region.

Once the first implant 970 has been modified, and flow has beenrestored, a further procedure may be performed. If the deposition ofanother material, such as an embolic material, contrast agent, or drug,is recommended for the target body region, such material can then bedeposited toward the target region. For example, after revascularizingthe vessel, the clinician can deposit additional material, e.g.,therapeutic material, toward the target region without delivering anadditional implant to at least partially occlude the vessel. However, insome embodiments, the injection of additional material can include usingand/or placing a second implant in the vessel. The second implant cancomprise any of the implants disclosed herein or be operated using anyof the methods disclosed herein, such as any of the methods or treatmentprocedures illustrated in FIGS. 17A-22.

Referring to FIGS. 24A-24B, whether or not a further material isinjected into the lumen, a second implant 980 can be placed proximallyof the first implant within the lumen. In some embodiments, the secondimplant 980 can be configured to fit within the lumen of the firstimplant. Further, in some embodiments, such as that illustrated in FIG.24A, the piercing or opening of the distal portion of the first implant970 can be performed by using the catheter 982 used to deliver thesecond implant 980. For example, the distal end of the catheter 982 canbe advanced distally through the distal portion of the first implant970, thus opening the first implant 970 in a manner similar to thatdiscussed above with respect to FIGS. 23A-23B.

In the embodiment shown in FIG. 24A, modification of the first implant970 and the further treatment of the target body region can be performedby modifying, penetrating, or punching a hole or aperture into the firstimplant 970 in a central location of the distal portion of the firstimplant 970, as noted above, and positioning a distal portion of thesecond implant 980 within the first implant 970. However, the valvecomponent of the first implant 970 can be maintained interconnected withat least a portion of the first implant 970, such as with the covermember or frame member. Thus, after being dislocated relative to thefirst implant, the valve component can remain attached to the firstimplant 970, thereby preventing release of the valve component intodistal vasculature. Later use of embolic material, glue, or other suchmaterials can allow the dislocated valve component to be more securelyfixed or adhered relative to the first implant 970.

In some embodiments, the second implant 980 can be coupled to orattached to the first implant 970 when released into the lumen. Forexample, the second implant 980 can sit entirely within the firstimplant 970. However, a distal portion of the second implant 980 can beconfigured to extend distally beyond the distal portion of the firstimplant 970 to facilitate passage of a material therethrough.

The second implant 980 can then be used in a manner as discussed hereinwith respect to other embodiments, such as for providing a material to adownstream target region.

Additionally, although the illustrated methods and procedures shown anddescribed with respect to FIGS. 17A-24B illustrate embodiments in whichthe implant comprises a helical support component that can be coupled toa catheter (see e.g., FIGS. 3-12B), such methods and procedures can alsobe implemented using an implant that has a deflectable support componentthat can be at advanced within a catheter (see e.g., FIGS. 13-16B).Further, any of the valve components disclosed herein (see e.g., FIGS.7A-16B) can be used with a helical support component that can be coupledto a catheter (as shown in FIGS. 3-12B) or a deflectable supportcomponent that can be at advanced within a catheter (as shown in FIGS.13-16B), including any combinations or modifications thereof.

According to various aspects of the subject technology, implantsdisclosed herein may be used for various applications for reducing orstopping flow through a luminal structure in a patient and inducinginfarction of a target tissue. Implants of the subject technology may beused for rapid, well-controlled, and reliable occlusion of luminalstructures. For example, the luminal structure may comprise at least oneof a blood vessel, a body organ, a lung, an airway, a Fallopian tube, acervical canal, a vagina, a cervix, a vas deferens, a bronchus, aureter, a colon, a rectum, an anus, a bio duct, a pancreatic duct, orother suitable tubular structures known to those of ordinary skill inthe art. In some embodiments, implants of the present disclosure may beused for temporary occlusion in cases of lung disease, or for temporaryocclusion of female reproductive organs for contraceptive purposes. Insome embodiments, implants of the present disclosure may be removed, orflow may be restored through the luminal structure to restore originalorgan functions.

In addition to the applications mentioned above, some embodiments of theimplants of the present disclosure may be used for various endoluminalocclusion procedures, including procedures for the lungs (e.g.,selective endobronchial occlusion for lung reduction, occlusion ofbronchopleural or bronchocutaneous fistulas, endovascular occlusion ofpulmonary AVMs and fistulas or aortopulmonary anastomoses) andprocedures for reproductive organs (e.g., endoluminal occlusion of vasdeferens or Fallopian tubes for minimally-invasive contraceptiveintervention, endovascular occlusion of varicocele in males and lowabdominal gonadal veins for reducing or completely eliminating chronicpelvic pain syndrome in females). In some embodiments, implants of thepresent disclosure may be used for stopping blood loss from a damagedblood vessel, closing an abnormal blood vessel or a blood vesselsupplying a vascular anamaly, or interrupting blood supply to an organor part of an organ for permanent devascularization (e.g., closure ofsplenic artery in spleen laceration, devascularization of tissuesinvolved by neoplastic process, either pre-operatively or as apalliative measure). In some embodiments, implants of the presentdisclosure may be used for various endovascular (e.g., neural andperipheral) procedures, head and neck AVFs, dissecting intracranial andextracranial vessels, traumatic and non-traumatic vessel injury orrupture (e.g., pelvic hemorrhages in trauma patients, carotid blow-outin patients with head and neck cancers, hemorrhage induced by aneoplasia, etc.), and devascularization prior to (or as an alternativeto) surgical resection of various organs or tumors.

In certain embodiments, implants of the present disclosure may be usedfor various organs, including for example, the spleen (e.g.,endovascular occlusion as a preoperative intervention or as analternative to surgical resection with indications including traumatichemorrhage, hypersplenism, bleeding secondary to portal hypertension orsplenic vein thrombosis, and various disorders such as thalassemiamajor, thrombocytopenia, idiopathic thrombocytopenic purpura, Gaucherdisease, and Hodgkin disease), the liver (e.g., occlusion of portalveins collaterals as adjunct to transjugular intrahepatic portosystemicshunt (“TIPS”), occlusion of the TIPS itself in cases of encephalopathy,occlusion of intrahepatic arterioportal fistulas), the kidney (e.g.,endoluminal ureteral occlusion for intractable lower urinary tractfistula with urine leakage, or for the treatment of uretero-arterialfistulae, endovascular occlusion as an alternative to surgical resectionfor end-stage renal disease or renovascular hypertension requiringunilateral or bilateral nephrectomy and renal transplant with nativekidneys in situ), and the heart (e.g., occlusion of coronary AVFs,transarterial embolization of Blalock-Taussig shunts). The applicationof implants of the present disclosure is not limited to applications forhuman patients, but may also include veterinary applications.

According to various embodiments of the subject technology, a covercomponent of an implant may be used to occlude, partially or completely,luminal structure in which a respective implant is deployed. In someembodiments as used herein, occlusion may refer to either partial orcomplete occlusion. In some embodiments, cover components can compriseat least one of a polyurethane, a polyanhidrate, PTFE, ePTFE, silicone,and other suitable materials known to those of ordinary skill in theart. In some embodiments, cover components may be elastic. In someembodiments, cover components may be permeable or non-permeable.

In some embodiments, an average thickness of a cover component can bebetween about 0.0005 inches and about 0.006 inches. In some aspects, theaverage thickness of a cover component may be less than about 0.0005inches or greater than about 0.006 inches. In certain embodiments, anaverage thickness of a distal portion of a cover component is greaterthan an average thickness of a proximal portion of a cover component.Such a configuration may ensure that more flow may be reduced at thedistal portion of a cover component. In some embodiments, the averagethickness of the distal portion of a cover component is between about0.002 inches and about 0.012 inches. In some embodiments, the averagethickness of the distal portion of a cover component may be less thanabout 0.002 inches or greater than about 0.012 inches. In someembodiments, the average thickness of the proximal portion of a covercomponent is between about 0.0005 inches and about 0.006 inches. In someembodiments, the average thickness of the proximal portion of a covercomponent may be less than about 0.0005 inches or greater than about0.006 inches.

Some embodiments of the implant described herein can incorporate one ormore features of implants and/or implant deployment systems

The foregoing description is provided to enable a person skilled in theart to practice the various configurations described herein. While thesubject technology has been particularly described with reference to thevarious figures and configurations, it should be understood that theseare for illustration purposes only and should not be taken as limitingthe scope of the subject technology.

There may be many other ways to implement the subject technology.Various functions and elements described herein may be partitioneddifferently from those shown without departing from the scope of thesubject technology. Various modifications to these configurations willbe readily apparent to those skilled in the art, and generic principlesdefined herein may be applied to other configurations. Thus, manychanges and modifications may be made to the subject technology, by onehaving ordinary skill in the art, without departing from the scope ofthe subject technology.

It is understood that the specific order or hierarchy of steps in theprocesses disclosed is an illustration of exemplary approaches. Basedupon design preferences, it is understood that the specific order orhierarchy of steps in the processes may be rearranged. Some of the stepsmay be performed simultaneously. The accompanying method claims presentelements of the various steps in a sample order, and are not meant to belimited to the specific order or hierarchy presented.

As used herein, the phrase “at least one of” preceding a series ofitems, with the term “and” or “or” to separate any of the items,modifies the list as a whole, rather than each member of the list (i.e.,each item). The phrase “at least one of” does not require selection ofat least one of each item listed; rather, the phrase allows a meaningthat includes at least one of any one of the items, and/or at least oneof any combination of the items, and/or at least one of each of theitems. By way of example, the phrases “at least one of A, B, and C” or“at least one of A, B, or C” each refer to only A, only B, or only C;any combination of A, B, and C; and/or at least one of each of A, B, andC.

Terms such as “top,” “bottom,” “front,” “rear” and the like as used inthis disclosure should be understood as referring to an arbitrary frameof reference, rather than to the ordinary gravitational frame ofreference. Thus, a top surface, a bottom surface, a front surface, and arear surface may extend upwardly, downwardly, diagonally, orhorizontally in a gravitational frame of reference.

Furthermore, to the extent that the term “include,” “have,” or the likeis used in the description or the claims, such term is intended to beinclusive in a manner similar to the term “comprise” as “comprise” isinterpreted when employed as a transitional word in a claim.

The word “exemplary” is used herein to mean “serving as an example,instance, or illustration.” Any embodiment described herein as“exemplary” is not necessarily to be construed as preferred oradvantageous over other embodiments.

A reference to an element in the singular is not intended to mean “oneand only one” unless specifically stated, but rather “one or more.”Pronouns in the masculine (e.g., his) include the feminine and neutergender (e.g., her and its) and vice versa. The term “some” refers to oneor more. Underlined and/or italicized headings and subheadings are usedfor convenience only, do not limit the subject technology, and are notreferred to in connection with the interpretation of the description ofthe subject technology. All structural and functional equivalents to theelements of the various configurations described throughout thisdisclosure that are known or later come to be known to those of ordinaryskill in the art are expressly incorporated herein by reference andintended to be encompassed by the subject technology. Moreover, nothingdisclosed herein is intended to be dedicated to the public regardless ofwhether such disclosure is explicitly recited in the above description.

While certain aspects and embodiments of the inventions have beendescribed, these have been presented by way of example only, and are notintended to limit the scope of the inventions. Indeed, the novel methodsand systems described herein may be embodied in a variety of other formswithout departing from the spirit thereof. The accompanying claims andtheir equivalents are intended to cover such forms or modifications aswould fall within the scope and spirit of the inventions.

What is claimed is:
 1. A method for treating a subject diagnosed with acancer, comprising: advancing an implant to a target region of a bodylumen which is near or contains the cancer, the implant having first andsecond sections engaged with a catheter at respective first and secondengagement points; releasing the implant first section from engagementwith the catheter at the first engagement point; permitting the implantfirst section to expand against a lumen wall at the target region suchthat the lumen becomes at least substantially occluded; and injecting atherapeutic material through a portion of the implant, wherein thematerial is effective to treat the cancer.
 2. The method of claim 1,wherein the implant first section comprises an implant distal section,and wherein the releasing comprises disengaging a first engagementmember from the distal section.
 3. The method of claim 1, wherein theportion of the implant comprises a valve component and the permittingcomprises causing the valve component to contact a distal end of thecatheter such that the catheter distal end moves the valve component toan open position.
 4. The method of claim 3, wherein the injectingcomprises advancing the material out through the valve component afterthe valve component is in the open position.
 5. The method of claim 1,further comprising, after the material is injected into the lumen,releasing the implant second section and moving the catheter proximallyrelative to the implant such that the valve component moves to a closedposition.
 6. The method of claim 5, wherein the moving the catheterrelative to the implant comprises proximally withdrawing the catheterwithin the lumen.
 7. The method of claim 1, further comprising, prior toreleasing the implant first section, releasing a blocking implant intocontact against the lumen wall downstream of the target region, theblocking implant occluding flow through the lumen beyond the targetregion.
 8. The method of claim 7, further comprising, after injectingthe material, allowing the material to flow into the target region, andremoving the blocking implant from the lumen.
 9. The method of claim 1,wherein the material comprises a nanoparticle, a radioemboliccomposition, a blood substitute comprising oxygen, a photothermal agent,or a chemotherapeutic.
 10. The method of claim 9, wherein thenanoparticle is a gold nanoparticle or a gold-iron oxide alloynanoparticle.
 11. The method of claim 9, wherein the nanoparticle islinked to a pH low-insertion peptide or to an antibody which binds anantigen expressed on a cell of the cancer.
 12. The method of claim 1,wherein the catheter comprises an optical fiber which extends from theproximal to the distal end of the catheter and wherein the optical fibercan emit infrared light from the distal end of the catheter.
 13. Themethod of claim 17, wherein the optical fiber is activated to emitinfrared light from the distal end of the catheter after injecting thematerial into the target region or after injecting the material into thetarget region and before moving the blocking implant from the lumen. 14.The method of claim 1, wherein the therapeutic material comprises aradiosensitizer.
 15. The method of claim 14, further comprisingadministering to the subject x-irradiation or γ-irradiation, wherein thex-irradiation or γ-irradiation is administered externally or internallythrough the catheter to the target region.
 16. A method for treating asubject diagnosed with a cancer, comprising: removing an occlusion at adistal end of an implant deployed within a body lumen upstream of atarget region which is near or includes the cancer, thereby restoringflow through the lumen to the target region; and after removing theocclusion from the implant, injecting a therapeutic material into thelumen such that the material passes through the implant to the targetregion, wherein the therapeutic material is effective to treat thecancer.
 17. The method of claim 16, wherein contacting the implantcomprises advancing an adjustment member through the implant to pierce acover component of the implant.
 18. The method of claim 17, wherein theadjustment member comprises a catheter and the advancing comprisesadvancing the catheter through the implant to pierce a cover componentof the implant.
 19. The method of claim 16, wherein the implant is afirst implant, and the method further comprises: after contacting thefirst implant, advancing a second implant to the target region, thesecond implant having first and second sections engaged with a catheterat respective first and second engagement points; releasing the firstsection from engagement with the catheter at the first engagement point;and before injecting the therapeutic material, permitting the implantfirst section to expand against a lumen wall at the target region suchthat the lumen becomes at least substantially occluded.
 20. The methodof claim 16, wherein contacting the first implant comprises contacting amesh component of the first implant with a material to dissolvecoagulated material on the mesh component, thereby restoring flowthrough the mesh component.